Published OnlineFirst July 2, 2010; DOI: 10.1158/1078-0432.CCR-10-0570 Published OnlineFirst on August 24, 2010 as 10.1158/1078-0432.CCR-10-0570 Report from the FDA Clinical Cancer Research U.S. Food and Drug Administration Approval: Ofatumumab for the Treatment of Patients with Chronic Lymphocytic Leukemia Refractory to Fludarabine and Alemtuzumab Steven J. Lemery1, Jenny Zhang2, Mark D. Rothmann2, Jun Yang3, Justin Earp3, Hong Zhao3, Andrew McDougal1, Anne Pilaro1, Raymond Chiang1, Joseph E. Gootenberg1, Patricia Keegan1, and Richard Pazdur1 Abstract Purpose: To describe the data and analyses that led to the U.S. Food and Drug Administration (FDA) approval of ofatumumab (Arzerra, GlaxoSmithKline) for the treatment of patients with chronic lympho- cytic leukemia (CLL) refractory to fludarabine and alemtuzumab. Experimental Design: The FDA reviewed the results of a planned interim analysis of a single-arm trial, enrolling 154 patients with CLL refractory to fludarabine, and a supportive dose-finding, activity-estimat- ing trial in 33 patients with CLL. Patients in the primary efficacy study received ofatumumab weekly for eight doses, then every 4 weeks for an additional four doses; patients in the supportive trial received four weekly doses. In the primary efficacy study, endpoints were objective response rate and response duration. Results: For regulatory purposes, the primary efficacy population consisted of 59 patients with CLL refractory to fludarabine and alemtuzumab. In this subgroup, the investigator-determined objective response rate was 42% [99% confidence interval (CI), 26–60], with a median duration of response of 6.5 months (95% CI, 5.8–8.3); all were partial responses. The most common adverse reactions in the primary efficacy study were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. Infusion reactions occurred in 44% of patients with the first infusion (300 mg) and 29% with the second infusion (2,000 mg). The most com- mon serious adverse reactions were infections, neutropenia, and pyrexia. Conclusions: On October 26, 2009, the FDA granted accelerated approval to ofatumumab for the treatment of patients with CLL refractory to fludarabine and alemtuzumab, on the basis of demonstration of durable tumor shrinkage. Clin Cancer Res; 16(17); 4331–8. ©2010 AACR. Chronic lymphocytic leukemia (CLL) is a clonal disor- patients with CLL has been based on a clinically mean- der of B cells with a variable clinical course. Median sur- ingful prolongation of progression-free survival (PFS) ac- vival is longer than 10 years4; however, reported median companied by an acceptable safety profile; whereas survival is only 2 to 3 years for patients with high-risk accelerated approval has been granted on the basis of disease (Rai category III or IV or Binet stage 3; ref. 1). Re- durable overall response rates (ORR) in patients with ported survival in CLL patients whose disease is refractory CLL, which has progressed following available therapy. to multiple drugs is shorter; in one report, median survival In order to be considered for accelerated approval, a was 8 months in patients with CLL refractory to fludara- drug that shows an effect on a surrogate endpoint that bine and alemtuzumab (2). is reasonably likely to predict clinical benefit must treat In the past decade, regular U.S. Food and Drug a serious or life-threatening disease or condition and Administration (FDA) approval for the treatment of show an advantage over available therapy (3). Addition- ally, the commercial manufacturer must commit to study the drug further to verify and characterize the pre- Authors' Affiliations: 1Office of Oncology Drug Products, Office of New dicted clinical benefit (3). Drugs; 2Office of Biostatistics; and 3Office of Clinical Pharmacology, Alemtuzumab received accelerated approval in 2001 Center for Drug Evaluation and Research, U.S. Food and Drug and regular approval in 2007. Accelerated approval was Administration, Silver Spring, Maryland based on the results of three single-arm studies enrolling Corresponding Author: Steven Lemery, Division of Biological Oncology Products, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 2374, Silver Spring, MD 20993. Phone: 301-796-2276; Fax: 301-796-9849; E-mail: [email protected]. 4 Horner MJ, Ries LAG, Krapcho M, et al., editors. SEER Stat Fact Sheets, doi: 10.1158/1078-0432.CCR-10-0570 1975-2006. Bethesda (MD): National Cancer Institute; [cited 2007 Jul ©2010 American Association for Cancer Research. 27]. Available from: http://seer.cancer.gov/. www.aacrjournals.org 4331 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst July 2, 2010; DOI: 10.1158/1078-0432.CCR-10-0570 Lemery et al. 149 patients with CLL and progressive disease following Nonclinical Pharmacology and Toxicology alkylating agents and fludarabine. The rates of durable objective responses (ORR) in the three studies ranged Ofatumumab binds specifically to the CD20 molecule, from 21 to 33% (4). Regular approval was based on supe- which is expressed on normal B lymphocytes (pre-B– to rior PFS [HR 0.58 (95% confidence interval [CI], 0.43– mature B–lymphocyte) and on B-cell CLL tumor cells. 0.77), P < 0.0001 stratified log-rank test] in a randomized The CD20 molecule is not shed from the cell surface active-controlled study comparing alemtuzumab to chlor- and is not internalized following antibody binding (6). ambucil in previously untreated patients with CLL (4). The Fab domain of ofatumumab binds to the CD20 Alemtuzumab also showed an improvement in ORR molecule, and the Fc domain mediates immune effector (83% versus 55%) and complete response rates (24% functions to result in B-cell lysis in vitro (6). Possible me- versus 2%) compared with chlorambucil (4). chanisms of action for ofatumumab include complement- The FDA approved bendamustine in 2008 on the basis dependent cytotoxicity and antibody-dependent cell- of superior PFS [HR 0.27 (95% CI, 0.17-0.43), P < 0.0001] mediated cytotoxicity. in a randomized active-controlled study comparing bend- Nonclinical data submitted in support of the applica- amustine to chlorambucil in previously untreated patients tion included tissue-binding studies in human and cyno- with CLL. In the study, bendamustine also showed an molgus monkey tissue panels, evaluation of in vitro improvement in ORR (59% versus 26%) and complete pharmacologic activity (receptor binding, lysis of CD20- response rates (8% versus <1%) compared with chloram- expressing cells), in vivo pharmacologic activity (antitumor bucil (5). activity in severe combined immunodeficient mice bearing In addition to bendamustine and alemtuzumab, the fol- human tumor xenografts, characterization of B-cell deple- lowing drugs are approved for the treatment of patients tion in treated monkeys), pharmacokinetic studies in cy- with CLL: fludarabine, cyclophosphamide, and chloram- nomolgus monkeys, and subacute (4-week) and chronic bucil. These drugs were approved on the basis of durable (7-month) toxicology studies in cynomolgus monkeys. objective tumor responses prior to the codification of the The major ofatumumab toxicities observed in nonclinical accelerated approval regulations. studies were extensions of its expected pharmacologic The Biologics License Application (BLA) for ofatumu- activity, that is, the severe and prolonged depletion of mab was submitted on January 30, 2009. The application B lymphocytes both in the circulation and in the major contained the interim results of a single-arm, fixed-dose, lymphoid organs (follicular germ centers of the spleen, multicenter trial (Hx-CD20-406), and the final results cortical lymph nodes, and Peyer's patches in the gastroin- of a multicenter, sequential dose-escalating cohort and testinal tract). Other toxicities observed in the 7-month re- activity-estimating trial (Hx-CD20-402), which used a peat-dose cynomolgus monkey toxicity study included shorter treatment duration (4 doses versus 12 doses) than sporadic, nonsevere infusion reactions, hematologic the primary efficacy study. Both trials enrolled adults with changes including B-cell depletion, mild hemolytic ane- CLL who had relapsed following, or were refractory to, mia, and changes in neo- and recall-antigen responses. one or more standard treatments. The BLA was supported by safety information from several trials enrolling 151 patients with follicular lymphoma or diffuse large B-cell Clinical Pharmacology lymphoma, 282 patients with rheumatoid arthritis or chronic obstructive pulmonary disease, and 28 patients Pharmacokinetic data were obtained from 146 patients with CLL who received ofatumumab in combination with with refractory CLL who received a 300-mg initial dose chemotherapy. The primary efficacy trial used the highest followed by seven weekly and four monthly infusions of dose and longest duration of ofatumumab in the clinical 2,000 mg (6). The Cmax and AUC(0−∞) after the eighth safety database. infusion in study Hx-CD20-406 were approximately 40% and 60% higher than after the fourth infusion in study Hx-CD20-402 (6). The mean volume of distribution Chemistry, Manufacturing, and Controls at steady-state (Vss) values ranged from 1.7 to 5.1 L (6). Ofatumumab is eliminated through both a target- Ofatumumab is an immunoglobulin G1 (IgG1) kappa independent route and a B-cell–mediated route (6). Ofa- human monoclonal