A Phase I Trial of Lenalidomide in Patients with Recurrent Primary Central Nervous SystemTumors Howard A. Fine, 1 Lyndon Kim, 1 PaulS.Albert, 3 J. Paul Duic, 1 Hilary Ma, 1 Wei Zhang, 1 TanyiforTohnya, 2 William D. Figg, 2 andCherylRoyce 1 Abstract Purpose: Inhibitionofangiogenesisrepresentsapromisingnewtherapeuticstrategyfortreating primary malignant brain tumors. Lenalidomide, a potent analogue of the antiangiogenic agent thalidomide, has shown significant activity in several hematologic malignancies, and therefore we chose to explore its tolerability and activity in patients with primary central nervous system tumors. Experimental Design: A phase I interpatient dose escalation trial of lenalidomide in patients withrecurrent primary centralnervous system tumors was conducted. Results: Thirty-six patients were accrued to the study, of which 28 were evaluable for toxicity, the primary end point of the trial.We show that lenalidomide can be given safely up to doses of 20 mg/m 2 , with the only toxicity being a probable increased risk of thromboembolic disease. Pharmacokinetic studies reveal good bioavailability, linear kinetics, and no effects of enzyme- inducing antiepileptic drugs on the metabolism of lenalidomide. No objective radiographic responses were seen in any of the treated patients. In the group of 24 patients with recurrent glioblastoma, the median time to tumor progression was <2 months and only 12.5% of patients were progression-free at 6 months. Conclusion: Lenalidomide is well tolerated in patients with recurrent glioma in doses up to 20 mg/m 2 . Treatment may be associated with an increased risk of thromboembolic disease. Preliminary data suggest that single agent activity may be limited in patients with recurrent glioblastoma at the doses evaluated although larger studies will be needed to confirm these observations. Despite recent advances in neurosurgery, radiotherapy, and chemotherapy, the prognosis of patients with malignant gliomas remains poor (1). With the failure of most standard cytotoxic agents to dramatically alter the course of this disease, there is an increasing interest in developing new therapeutics with novel mechanisms of action. Preclinical and clinical studies have shown that gliomas are highly angiogenic and that antiangiogenic therapy represents a potentially promising new therapeutic strategy (2–7). Thalid- omide was one of the first oral antiangiogenic agents evaluated in patients with recurrent malignant gliomas (8). As a single agent, thalidomide showed cytostatic activity against gliomas, as reflected by stabilization of disease in some patients (9). Unfortunately, ‘‘responses’’ to thalidomide were generally short-lived, leading to the search for similar but potentially more clinically active agents. Lenalidomide (Revlimid, CC-5013) is a potent thalidomide analogue based on in vitro anti-inflammatory and immuno- modulatory assays (10–13). Lenalidomide has shown signif- icant antitumor activity in patients with multiple myeloma and myelodysplastic syndrome with chromosome 5q deletions (14–18). Secondary to lenalidomide safety profile, proven activity in several other cancers, and the possible antiglioma activity of thalidomide, we elected to evaluate lenalidomide in patients with recurrent gliomas. Patients and Methods Study population and eligibility criteria. Patients 18 years or older with histologically confirmed diagnosis of progressive or recurrent primary central nervous system tumors who had failed prior radiation therapy were eligible for the study. Evaluable disease on magnetic resonance imaging scan, a Karnofsky performance status of z60%, and normal hematologic, liver, and renal function were required. The number or types of prior treatment regimens was not an exclusion criterion except for patients who had prior therapy with thalidomide. All participants signed a written informed consent approved by the National Cancer Institute Institutional Review Board. Treatment. Each 4-week treatment cycle consisted of lenalidomide administered p.o. once daily for 3 weeks followed by a 1-week rest period. A complete physical and neurologic examination was done Cancer Therapy: Clinical Authors’Affiliations: 1 Neuro-Oncology Branch and 2 Medical Oncology Branch, National Cancer Institute; and 3 Biometric Research Branch,The National Institute of Neurological Disorders and Stroke, Bethesda, Maryland Received6/22/07;revised8/29/07;accepted9/7/07. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.This article must therefore be hereby marked advertisement in accordance with18U.S.C.Section1734solely toindicatethisfact. Requestsforreprints: HowardA.Fine,Neuro-OncologyBranch,NationalCancer Institute, 9030 Old Georgetown Road, Bethesda, MD 20892. Phone: 301-402- 6383;Fax:301-480-2246;E-mail:hfine@mail.nih.gov. F 2007AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-07-1546 www.aacrjournals.org Clin Cancer Res 2007;13(23) December1, 2007 7101 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/13/23/7101/1973038/7101.pdf by guest on 17 August 2023