APhase I T rialof Lenalidomide in Patients with Recurrent Primary
Central Nervous SystemT umors
Howard A. Fine,1Lyndon Kim,1Paul S. Albert,3J. Paul Duic,1Hilary Ma,1Wei Zhang,1
Tanyifor Tohnya,2William D. Figg,2and Cheryl Royce1
Purpose:Inhibitionofangiogenesis represents apromisingnew therapeutic strategy for treating
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
Experimental Design: A phase I interpatient dose escalation trial of lenalidomide in patients
with recurrent 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/m2, 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 only12.5% of patients
were progression-free at 6 months.
Conclusion: Lenalidomide is well tolerated in patients with recurrent glioma in doses up to
20 mg/m2. 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
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.
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
Patients 18 years or older
Cancer Therapy: Clinical
Authors’Affiliations:1Neuro-Oncology Branch and2Medical Oncology Branch,
National Cancer Institute; and3Biometric Research Branch,The National Institute
of Neurological Disorders and Stroke, Bethesda, Maryland
Received 6/22/07; revised 8/29/07; accepted 9/7/07.
The costs of publicationof this articlewere defrayedinpart by the paymentof page
charges.This article must therefore be hereby marked advertisement in accordance
with18 U.S.C. Section1734 solely toindicatethis fact.
Institute, 9030 Old Georgetown Road, Bethesda, MD 20892. Phone: 301-402-
6383; Fax: 301-480-2246; E-mail: firstname.lastname@example.org.
F2007 American Association for Cancer Research.
www.aacrjournals.orgClin Cancer Res 2007;13(23) December1, 20077101
Cancer Therapy: Clinical
www.aacrjournals.org Clin Cancer Res 2007;13(23) December1, 20077106
1. DeAngelisLM.Braintumors.NEnglJMed2001 ;344:
2. Plate KH, Breier G,Weich HA, et al.Vascularendothe-
lial growth factor is a potential tumour angiogenesis
factor in human gliomas in vivo. Nature 1992;359:
3. Zagzag D, Miller DC, SatoY, et al. Immunohistoche-
mical localization of basic fibroblast growth factor in
astrocytomas. Cancer Res1990;50:7393^8.
4. Takahashi JA, Mori H, Fukumoto M, et al. Gene
expression of fibroblast growth factors inhuman glio-
mas and meningiomas: demonstration of cellular
source of basic fibroblast growth factor mRNA and
peptide in tumor tissues. Proc Natl Acad Sci U S A
5. Millauer B, Shawver LK, Plate KH, et al. Glioblastoma
growth inhibited in vivo by a dominant-negative Flk-1
6. Maxwell M, Naber SP,Wolfe HJ, et al. Expression
of angiogenic growth factor genes in primary human
7. Purow B, Fine HA. Antiangiogenic therapy forprima-
ry and metastatic brain tumors. Hematol Oncol Clin
North Am 2004;18:1161^81, x.
8. D’ Amato RJ, Loughnan MS, Flynn E, et al. Thalido-
mide is an inhibitor of angiogenesis. Proc Natl Acad
Sci US A1994;91:4082^5.
9. Fine HA, FiggWD, Jaeckle K, et al. Phase II trial of
the antiangiogenic agent thalidomide in patients with
recurrent high-grade gliomas. J Clin Oncol 2000;18:
10. Sampaio EP, Sarno EN, Galilly R, et al.Thalidomide
selectively inhibits tumor necrosis factor a production
by stimulated human monocytes. J Exp Med 1991;
11. Dredge K, Horsfall R, Robinson SP, et al. Orally
administered lenalidomide (CC-5013) is anti-angio-
genic in vivo and inhibits endothelial cell migration
and Akt phosphorylation in vitro. Microvasc Res
12. Haslett PA, Corral LG, Albert M, et al. Thalidomide
costimulates primary humanT lymphocytes,preferen-
tially inducing proliferation, cytokine production, and
cytotoxic responses in the CD8+ subset. J Exp Med
13. BartlettJB, Michael A, Clarke IA, et al. PhaseIstudy
to determine the safety, tolerability andimmunostimu-
latory activity of thalidomide analogue CC-5013 in
patients with metastatic malignant melanoma and
14. Chanan-Khan A, Miller KC, Musial L, et al. Clinical
efficacy of lenalidomide in patients with relapsed or
refractory chronic lymphocytic leukemia: results of a
phase IIstudy. JClin Oncol 2006;24:5343^9.
15. ChoueiriTK, Dreicer R, Rini BI, et al. Phase II study
of lenalidomide in patients with metastatic renal cell
carcinoma. Cancer 2006;107:2609^16.
16. Richardson PG, Blood E, Mitsiades CS, et al. A ran-
domized phase 2 study of lenalidomide therapy for
patients with relapsed or relapsed and refractory
multiple myeloma. Blood 2006;108:3458^64.
17.TohnyaTM, Ng SS, DahutWL, et al. A phase I study
of oral CC-5013 (lenalidomide, Revlimid), a thalido-
mide derivative, in patients with refractory metastatic
cancer. Clin Prostate Cancer 2004;2:241^3.
18. List A, Dewald G, Bennett J, et al. Lenalidomide in
the myelodysplastic syndrome with chromosome 5q
deletion. NEnglJMed 2006;355:1456^65.
of CC-5013, an analogue of thalidomide, in human
plasma by liquid chromatography-mass spectrometry.
20. Fine HA, Wen PY, Maher EA, et al. Phase II trial
of thalidomide and carmustine for patients with recur-
rent high-grade gliomas. J Clin Oncol 2003;21:
21. Chang SM, Lamborn KR, Malec M, et al. Phase II
studyof temozolomide and thalidomide withradiation
therapy fornewly diagnosed glioblastoma multiforme.
IntJRadiat Oncol Biol Phys 2004;60:353^7.
22. Groves MD, PuduvalliVK, Chang SM, et al. ANorth
American brain tumor consortium (NABTC 99-04)
phase II trial of temozolomide plus thalidomide for re-
current glioblastoma multiforme. J Neurooncol 2007;
23. Bartlett JB, Dredge K, Dalgleish AG.The evolution
of thalidomide and its IMiD derivatives as anticancer
agents. Nat Rev Cancer 2004;4:314^22.
24. Dredge K, MarriottJB, Macdonald CD, et al. Novel
independently of immunomodulatory effects. Br J
25. Gupta D,Treon SP, ShimaY, et al. Adherenceofmul-
tiple myeloma cells to bone marrow stromal cells up-
regulates vascularendothelialgrowthfactor secretion:
therapeutic applications.Leukemia 2001 ;15:1950^61.
26.Walsh DC, Kakkar AK. Thromboembolism in brain
tumors. Curr Opin Pulm Med 2001 ;7:326^31.
28. Ballman KV, BucknerJC, Brown PD, et al.The rela-
tionship between six-month progression-free survival
and 12-month overall survival end points for phase II
trials in patients with glioblastoma multiforme. Neuro-