Download A Phase I Trial of Lenalidomide in Patients with Recurrent Primary

Cancer Therapy: Clinical
A Phase I Trial of Lenalidomide in Patients with Recurrent Primary
Central Nervous SystemTumors
Howard A. Fine,1 Lyndon Kim,1 Paul S. Albert,3 J. Paul Duic,1 Hilary Ma,1 Wei Zhang,1
Tanyifor Tohnya,2 William D. Figg,2 and Cheryl Royce1
Abstract
Purpose: Inhibition of angiogenesis represents a promising new 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
tumors.
Experimental Design: A phase I interpatient dose escalation trial of lenalidomide in patients
with recurrent primary central nervous 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 enzymeinducing 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/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
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). Thalidomide 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
Authors’ Affiliations: 1Neuro-Oncology Branch and 2Medical Oncology Branch,
National Cancer Institute; and 3Biometric 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 publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Howard A. Fine, Neuro-Oncology Branch, National Cancer
Institute, 9030 Old Georgetown Road, Bethesda, MD 20892. Phone: 301-4026383; Fax: 301-480-2246; E-mail: hfine@ mail.nih.gov.
F 2007 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-07-1546
www.aacrjournals.org
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 immunomodulatory assays (10 – 13). Lenalidomide has shown significant 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
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Cancer Therapy: Clinical
every 2 weeks for the first cycle and every 4 weeks thereafter. A magnetic resonance imaging scan was done before each cycle to assess
response. Patients with stable or responding disease based on clinical
and radiographic assessment continued on to an additional cycle
of treatment. Three patients per dose level were treated, and if no
dose-limiting toxicity (DLT) occurred, three subsequent patients were
enrolled in the next higher dose. If, however, a DLT was encountered,
three more patients would be added to that group. The maximum
tolerated dose was considered to have been exceeded in the event of two
DLTs (any drug-related nonhematologic grade z3 or hematologic grade
z4 toxicity) in any given dose level. The six dose levels were 2.5, 5, 8,
11, 15, and 20 mg/m2/d. Based on existing data showing severe and
life-threatening neutropenia with doses >40 mg/d, the maximum total
daily dose was predetermined to be <40 mg. DLT was defined for only
the first cycle of therapy (4 weeks) and patients had to have at least
4 weeks of treatment to be evaluable for toxicity and DLT.
Patients were stratified into those not on enzyme-inducing antiepileptic drugs (EIAED; group A) and those on EIAED (group B), with
each group proceeding through dose escalation independently. After
the pharmacokinetic data from patients on the second dose level
revealed that EIAEDs had no effects on lenalidomide metabolism, the
protocol was amended to place all subsequent patients into a single
stratum.
Pharmacokinetic evaluation. Serial blood samples for the determination of lenalidomide were collected on the 1st and 15th days of the
first cycle. Plasma concentrations of lenalidomide were measured using
a high-performance liquid chromatography-mass spectrometry method
and analyzed as previously described (19).
Statistical considerations. The primary end point was to evaluate the
toxicity and pharmacokinetics of lenalidomide in this dose-escalating
phase I study. Using the dose escalation scheme described above, the
probability of escalating to the next dose level, based on the true rate of
DLT at the current dose, is given by the following (each group was
considered independent of the other):
True toxicity at
a given dose
Probability of
escalating
10%
20%
30%
40%
50%
60%
0.91
0.71
0.49
0.31
0.17
0.08
Thus, if the true underlying proportion of DLTs is 50% at the current
dose, there was a 17% chance of escalating to the next dose. The
progression-free survival (PFS) and overall survival rate were estimated
according to the method of Kaplan and Meier.
Pharmacokinetic analysis. Any difference in dose-normalized AUC0-a
between patients with and without coadministration of EIAEDs was
determined by Mann-Whitney U test. Kruskal-Wallis one-way ANOVA
was used to determine differences in CL/F (and dose-normalized
AUC0-a) as dose was increased. Linear regression analysis was carried
out on AUC0-a to determine dose proportionality. A Wilcoxon signedrank test was also used to determine if the ratio of accumulation is
equal to 1.0. Statistical evaluations were done on the NCSS 2001
software package (J.L. Hintze).
Results
Patients. A total of 36 patients were accrued to this trial
(23 males, 13 females). The median age for patients in both
groups was 48 years (range, 20-82 years). The median
Karnofsky performance status was 90%. Tumor histology
included 24 glioblastomas, 7 anaplastic gliomas, 3 low-grade
gliomas, 1 meningioma, and 1 hemangioblastoma. All patients
had recurrent disease following radiation therapy at a
minimum. The median number of prior chemotherapy
regimens was 2 (range, 0-6). Only patients who completed
the first 4 weeks of treatment or patients who experienced a
drug-related DLT before completion of the first 4 weeks of
treatment were considered evaluable for DLT and maximum
tolerated dose determination, the primary end point of the trial.
Twenty-seven of 36 patients were therefore evaluable for the
primary end point.
Pharmacokinetic analysis. Twenty-four patients had complete pharmacokinetic sampling done (Table 1). There was no
statistically significant difference in dose-normalized AUC0-1
(P = 0.8) evident between the patients on EIAEDs and those
who were not, and thus the EIAED and non-EIAED treatment
groups were combined for further pharmacokinetic and other
analyses. No difference (P = 0.27) was observed in CL/F (and
dose-normalized AUC0-a) as dose increased. In the dose range
investigated (2.5-20 mg/m2), lenalidomide exhibited apparent
linear pharmacokinetics. Linear regression analysis indicated a
dose-proportional increase in AUC0-a with a good correlation
(Fig. 1). The lenalidomide concentration-time profiles were
very similar between patients (Fig. 2) and were characterized by
a rapid absorption with mean T max of 1.0 h and a monophasic
decline with mean terminal half-life of 3.9 h.
Toxicities. Seven patients experienced clinical and radiographic progression before their first 4-week evaluation and
were therefore evaluable for toxicity but not maximum
tolerated dose determination. The drug was generally very well
tolerated with only one observed DLT (see Table 2). There were
only two episodes of grade 2 thrombocytopenia, one episode
each of grade 2 and grade 3 neutropenia. The one grade 3 neutropenia occurred in a patient previously treated with high-dose
Table 1. Mean (SD) pharmacokinetic variable estimates of lenalidomide
Dose (mg/m2)
Variables
2.5
AUC(0-1) (ngh/mL)
C max (ng/mL)
T max* (h)
t 1/2 (h)
CL/F (mL/min/m2)
V d/F (L/m2)
316
89.8
0.9
3.2
169
38.9
(155)
(49.2)
(0.5-2)
(1.8)
(103)
(12.1)
5
8
11
622 (333)
114 (56.0)
1.5 (1-2)
4.5 (5.5)
206 (182)
50.5 (36.9)
385 (261)
109 (84.9)
0.5 (0.5)
2.3 (0.4)
451 (307)
85.1 (45.3)
923 (479)
229 (145)
1.0 (1-2)
5.6 (4.4)
258 (148)
89.5 (29.1)
15
1055 (252)
409 (263)
1.0 (0.5-1)
2.2 (0.8)
247 (61.3)
45.8 (16.4)
20
942
210
0.5
2.5
354
77.8
*T max values are median (range).
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Lenalidomide in Recurrent Central Nervous SystemTumors
Fig. 1. Dose-proportional increase in AUC0-a.
chemotherapy and autologous bone marrow support. Mild
to moderate fatigue was seen in 13 patients. The only clinically significant infection was a case of herpes zoster keritoconjunctivitis. There were five cases of venous thrombosis
(18% of evaluable patients) including a case of retinal vein
thrombosis in the patient on lenalidomide for the longest time
(24 months). Adverse events did not seem to be dose related.
Clinical efficacy. Twenty-seven of 36 patients completed the
first 3 weeks of treatment and were therefore evaluable or
maximum tolerated dose determination. Of the nine patients
not evaluable, seven had rapid disease progression, one had a
DLT (herpes zoster), and one required a non – brain tumor and
non – study-related surgical procedure.
No patient had an objective radiographic response. The
6-month PFS for all 27 evaluable patients was 14.8% [95%
confidence interval (95% CI), 6.0-36.6%; Fig. 3A]. The median
time to progression for this group of patients was 1.74 months
(95% CI, 1.6-3.4) and the overall 6-month survival for all
evaluable patients was 45.8% (95% CI, 30.1-69.8%; Fig. 3B).
The median survival time was 5.95 months (95% CI, 4.4-11.4).
The 24 patients with glioblastoma, 17 of whom where
evaluable for response, represented a more homogeneous
subgroup to study. The 6-month PFS of these patients was
17.7% (95% CI, 6.3-49.3%) and the median time to
progression is 1.84 months (95% CI, 1.7-4.6; Fig. 4A). The
6-month overall survival was 47.1% (95% CI, 28.4-77.9%)
with a median survival of 5.95 months (95% CI, 4.4-11.4;
Fig. 4B). Seven glioblastoma multiforme patients were not
evaluable for the primary end points of this study because they
had disease progression before the end of the first cycle. If we
include these patients in the overall tumor efficacy cohort, the
overall 6-month PFS was 12.5%. There was no apparent
correlation between clinical outcome and dose of lenalidomide
or pharmacokinetic profiles.
prolonged disease stabilization in patients with recurrent
gliomas. In patients with newly diagnosed glioblastoma, overall
median survival was equivalent to that seen when carmustine is
used in the postradiation adjuvant setting. The lack of clear
convincing evidence of significant antiglioma activity, yet the
hint of some clinical benefit, has led to the search for drug
combinations incorporating thalidomide and more potent
thalidomide analogues.
Lenalidomide is a potent IMiDS (immunomodulatory
drugs), a class of drugs that are structural and functional
analogues of thalidomide. Lenalidomide has more immunomodulating and antiangiogenic activities than thalidomide in
various preclinical assays (10, 12, 23, 24). The precise
antiangiogenic mechanism of lenalidomide is unclear, although it has been shown that lenalidomide can inhibit
vascular endothelial growth factor – , basic fibroblast growth
factor – , and tumor necrosis factor-a – induced endothelial cell
migration (11). Additionally, it has been suggested that
thalidomide analogues like lenalidomide can inhibit tumorand stroma cell – mediated secretion of vascular endothelial
growth factor and basic fibroblast growth factor in preclinical
models of multiple myeloma (25). Thus, lenalidomide is a drug
of interest to investigate in patients with malignant gliomas.
Lenalidomide has shown significant activity in multiple
myeloma and in myelodysplasia with chromosome 5q deletion
(18). Dose and toxicity information from these trials may not,
however, be relevant to brain tumor patients because bone
marrow reserve is generally normal in these patients compared
with those with hematologic malignancies. To this end, at least
two single agent phase I trials of lenalidomide in patients with
solid tumors have partially been reported.
Bartlett et al. (13) conducted a phase I trial of lenalidomide in patients with solid tumors using an intrapatient weekly
dose escalation schema of 2 mg/d escalating to 50 mg/d over
4 weeks, although treatment was formally suspended after
4 weeks secondary to toxicity. Thus, dose versus toxicity data
were difficult to determine. Tohnya et al. (17) conducted a
phase I trial of lenalidomide in patients with refractory solid
tumors using a more standard modified Fibonacci design with
dose escalation from 5 to 40 mg/d. The investigators observed a
significant incidence of grade 1 and grade 2 fatigue, rash,
nausea, myalgias, and neutropenia. A number of grade 3 and 4
toxicities, including neutropenia, resulted in modifying the
Discussion
Thalidomide has been evaluated in a number of phase II
trials in patients with recurrent high-grade gliomas and in
patients with newly diagnosed glioblastomas in combination with and following standard fractionated radiotherapy
(9, 20 – 22). There was a suggestion of some antiglioma activity
with a few minor radiographic responses and several cases of
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Fig. 2. Concentration-time profile for a patient with recurrent high-grade glioma
on 11mg/m2 of oral lenalidomide.
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Table 2. Toxicity
Toxicity/adverse event
Grade 2/3/4 Common Toxicity Criteria toxicity
Dose level
1
Alanine aminotransferase
Platelets
Leukopenia
Hypokalemia
Neutropenia
Thrombosis/vascular (DVT)
Thrombocytopenia
Hypophosphatemia
Seizure
Fatigue
Vomiting
Nausea
Constipation
Diarrhea
Urinary tract infection
Herpes zoster
Keratitis
Rash
Dental abcess
Retinal vein occlusion
2
3
4
5
6
1/0/0
1/0/0
1/0/0
0/2/0
1/0/0
0/1/0
1/1/0
0/1/0
1/0/0
1/0/0
3/0/1
1/1/0
2/0/0
5/0/0
1/1/0
1/1/0
2/0/0
2/0/1
1/0/0
0/1/0
2/1/0
5/0/0
1/1/0
0/1/0
0/1/0
0/1/0
2/0/0
1/0/0
1/0/0
treatment regimen to administering lenalidomide for 21 days
on a 28-day cycle.
Based on these and other trials showing that continuous
dosing and higher doses of lenalidomide are not well tolerated,
we designed our phase I trial to use the accepted 21 days on and
7 days off dose administration schedule. Our pharmacokinetic
analysis revealed that lenalidomide exhibited rapid absorption
and displayed relatively good linear kinetics relative to the dose
administered and AUC. Additionally, no accumulation of drug
in the plasma was observed after multiple doses due to the
short terminal half-life of the agent. Finally, EIAEDs, known to
induce CYP450 enzymes such as CYP3A4, did not have any
effect on lenalidomide metabolism or exposure.
We found that lenalidomide was well tolerated at all doses
evaluated. Despite the relatively high doses of lenalidomide
used in this trial, we did not observe the neutropenia
commonly reported in other trials of lenalidomide. This likely
reflects the fact that most glioma patients are less heavily
pretreated with chemotherapy and thus have relatively better
bone marrow reserve than patients with multiple myeloma and
myelodysplastic syndrome, those patients most commonly
treated with lenalidomide.
Despite the immunosuppressive activity of lenalidomide, we
did not see any significant clinical infections except for one case
of herpes zoster of the trigeminal nerve. This infection,
however, occurred in a patient on long-term, high-dose
glucocorticoids, and thus the relationship of the infection to
lenalidomide is uncertain. We did, however, observe five cases
of venous thrombosis in patients treated with lenalidomide.
Although thalidomide and lenalidomide are known to increase
the risk of thromboembolic events in other disease settings,
glioma patients are at inherent high risk of developing
thromboembolic events independent of treatment (26). Thus,
it is impossible to know for certain whether lenalidomide
contributed to any of the thrombotic events observed in this
trial. Nevertheless, the fact that 18% of patients experienced a
Clin Cancer Res 2007;13(23) December 1, 2007
thromboembolic event during their relatively short duration of
exposure to lenalidomide is of concern and strongly suggests a
possible contribution of lenalidomide to the high thrombotic
rate seen in this trial.
Twenty-four glioblastoma patients with good performance
status (i.e., potentially phase II trial eligible) were treated on
this trial, allowing us to carry out an exploratory efficacy
analysis of the data despite the fact that the trial was not
formally designed to evaluate the antitumor efficacy of
lenalidomide. Because there were no objective radiographic
responses and no clear improvement in patient symptoms, PFS
in conjunction with clinical stability was our major determinant of clinical benefit. As shown in Fig. 3A, the median PFS for
all evaluable glioblastoma patients was 1.84 months and the
6-month PFS was 17.7%. If one includes all patients with
glioblastoma, including those who had tumor progression
during the first cycle, the 6-month PFS was 12.6% (Fig. 4A).
This compares to a historical 15% and 9% 6-month PFS for
patients accrued to phase I/II single institution and cooperative
group trials of drugs subsequently determined to be inactive in
glioblastoma, respectively (27, 28). Thus, these preliminary
data are not encouraging for the antitumor activity of lenalidomide for recurrent glioblastoma.
The lack of objective radiographic responses and a 6-month
PFS of 12.5% are disappointing; however, it remains plausible
that a study with a larger cohort of less heavily pretreated
patients might give a more favorable outcome. Nevertheless,
there are few data to suggest that prior exposure to standard
chemotherapeutic agents (almost exclusively alkylating agents)
lessens one’s likelihood of responding to an antiangiogenic
agent. Indeed, one of our few long-term responders was one of
our most heavily pretreated patients, having had four prior
chemotherapeutic regimens before his enrollment on this trial.
In addition to prior extensive prior treatment, another
possible explanation for the low response rate is that most
patients were treated at a dose of lenalidomide below the
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Lenalidomide in Recurrent Central Nervous SystemTumors
maximum tolerated dose. Nevertheless, a true dose-response
relationship was not seen in our cohort of patients and has
never been shown for thalidomide or lenalidomide. Indeed, one
of the few long-term stable disease patients in this study was
treated at our lowest dose (2.5 mg/m2). Given that all patients
on this trial were treated at doses of lenalidomide that have
proved active in lenalidomide-sensitive tumors, there is little
compelling data to believe that dose escalations higher than the
20 mg/m2 we achieved in this trial would result in greater
clinical benefit. Nevertheless, given the preliminary nature of
our efficacy data, a larger formal phase II trial of lenalidomide
in less heavily pretreated patients using the 20 mg/m2 dose, or a
higher dose as yet to be established, might be considered
reasonable.
We were unable to identify any radiographic or clinical
variables that could allow us to prospectively identify patients
likely to benefit from lenalidomide. Because the true in situ
antitumor and antiangiogenic mechanism of action of lenalidomide remains obscure, no obvious biological end points
could be evaluated. Recently, it has been suggested that
peripheral endothelial cell and endothelial cell progenitor cells
may be surrogate end points of angiogenesis in vivo; however,
these assays had not been identified at the time this trial was
conducted. The utility of such assays may represent a potential
area of exploration should additional trials of lenalidomide be
conducted in patients with recurrent glioma.
Fig. 4. A, PFS for evaluable glioblastoma multiforme (GBM) patients with 95%
CIs. B, overall survival for evaluable glioblastoma multiforme patients with 95% CIs.
Fig. 3. A, PFS for all evaluable patients with 95% CIs. B, overall survival for all
evaluable patients with 95% CIs.
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The minimal antitumor efficacy of lenalidomide observed
in our trial suggests that if lenalidomide ultimately does prove
to have significant clinical activity, trials with large numbers of
patients will likely be required to definitively show such
modest activity in a statistically rigorous way. The extensive
monetary and patient resources necessary for such a trial
might be better used on definitive trials of other more highly
active antiangiogenic agents that have recently shown significant radiographic responses and clinical benefit in ongoing
clinical trials of patients with recurrent gliomas (i.e.,
bevacizumab). A more promising approach for the development of lenalidomide in gliomas might be to consider trials
of lenalidomide in combination with other chemotherapeutic
agents (i.e., temozolomide and nitrosoureas), although additive myelosuppresion may ultimately limit the utility of such
combinations.
In summary, lenalidomide is generally well tolerated in
patients with recurrent primary central nervous system tumors
at doses up to and including 20 mg/m2, with the only major
toxicity being an increased risk of thromboembolic disease.
Although confirmatory phase II data may be necessary,
lenalidomide does not seem to be a highly effective single
agent for patients with recurrent glioblastoma at the doses
evaluated. Trials of lenalidomide in combination with other
agents may be worth exploring.
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References
1. DeAngelis LM. Brain tumors. N Engl J Med 2001;344:
114 ^ 23.
2. Plate KH, Breier G,Weich HA, et al.Vascular endothelial growth factor is a potential tumour angiogenesis
factor in human gliomas in vivo. Nature 1992;359:
845 ^ 8.
3. Zagzag D, Miller DC, Sato Y, et al. Immunohistochemical localization of basic fibroblast growth factor in
astrocytomas. Cancer Res 1990;50:7393 ^ 8.
4. Takahashi JA, Mori H, Fukumoto M, et al. Gene
expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular
source of basic fibroblast growth factor mRNA and
peptide in tumor tissues. Proc Natl Acad Sci U S A
1990;87:5710 ^ 4.
5. Millauer B, Shawver LK, Plate KH, et al. Glioblastoma
growth inhibited in vivo by a dominant-negative Flk-1
mutant. Nature 1994;367:576 ^ 9.
6. Maxwell M, Naber SP, Wolfe HJ, et al. Expression
of angiogenic growth factor genes in primary human
astrocytomas may contribute to their growth and progression. Cancer Res1991;51:1345 ^ 51.
7. Purow B, Fine HA. Antiangiogenic therapy for primary and metastatic brain tumors. Hematol Oncol Clin
North Am 2004;18:1161 ^ 81, x.
8. D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad
Sci U S A 1994;91:4082 ^ 5.
9. Fine HA, Figg WD, Jaeckle K, et al. Phase II trial of
the antiangiogenic agent thalidomide in patients with
recurrent high-grade gliomas. J Clin Oncol 2000;18:
708 ^ 15.
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;
173:699 ^ 703.
11. Dredge K, Horsfall R, Robinson SP, et al. Orally
administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration
and Akt phosphorylation in vitro. Microvasc Res
2005;69:56 ^ 63.
12. Haslett PA, Corral LG, Albert M, et al. Thalidomide
costimulates primary humanT lymphocytes, preferentially inducing proliferation, cytokine production, and
cytotoxic responses in the CD8+ subset. J Exp Med
1998;187:1885 ^ 92.
13. Bartlett JB, Michael A, Clarke IA, et al. Phase I study
to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in
patients with metastatic malignant melanoma and
other advanced cancers. BrJCancer 2004;90:955 ^ 61.
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 II study. J Clin Oncol 2006;24:5343 ^ 9.
15. Choueiri TK, 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 randomized 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, Dahut WL, et al. A phase I study
of oral CC-5013 (lenalidomide, Revlimid), a thalidomide 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. N Engl J Med 2006;355:1456 ^ 65.
19. TohnyaTM, Hwang K, Lepper ER, et al.Determination
of CC-5013, an analogue of thalidomide, in human
plasma by liquid chromatography-mass spectrometry.
Clin Cancer Res 2007;13(23) December 1, 2007
7106
J Chromatogr B AnalytTechnol Biomed Life Sci 2004;
811:135 ^ 41.
20. Fine HA, Wen PY, Maher EA, et al. Phase II trial
of thalidomide and carmustine for patients with recurrent high-grade gliomas. J Clin Oncol 2003;21:
2299 ^ 304.
21. Chang SM, Lamborn KR, Malec M, et al. Phase II
study of temozolomide and thalidomide with radiation
therapy for newly diagnosed glioblastoma multiforme.
Int J Radiat Oncol Biol Phys 2004;60:353 ^ 7.
22. Groves MD, Puduvalli VK, Chang SM, et al. A North
American brain tumor consortium (NABTC 99-04)
phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme. J Neurooncol 2007;
81:271 ^ 7.
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, Marriott JB, Macdonald CD, et al. Novel
thalidomide analogues display anti-angiogenic activity
independently of immunomodulatory effects. Br J
Cancer 2002;87:1166 ^ 72.
25. Gupta D,Treon SP, ShimaY, et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor 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.
27.Wong ET, Hess KR, Gleason MJ, et al. Outcomes and
prognostic factors in recurrent glioma patients enrolled
onto phase II trials. J Clin Oncol 1999;17:2572 ^ 8.
28. Ballman KV, Buckner JC, Brown PD, et al. The relationship between six-month progression-free survival
and 12-month overall survival end points for phase II
trials in patients with glioblastoma multiforme. NeuroOncol 2007;9:29 ^ 38.
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A Phase I Trial of Lenalidomide in Patients with Recurrent
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Clin Cancer Res 2007;13:7101-7106.
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