Online citations, reference lists, and bibliographies.

Phase I Study Of An Immunomodulatory Thalidomide Analog, CC-4047, In Relapsed Or Refractory Multiple Myeloma.

S. Schey, P. Fields, J. Bartlett, I. A. Clarke, G. Ashan, R. Knight, M. Streetly, A. Dalgleish
Published 2004 · Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
PURPOSE To assess the safety, efficacy, and immunomodulatory effects of CC-4047 (Actimid; Celgene, San Diego, CA) in patients with relapsed or refractory myeloma. PATIENTS AND METHODS Twenty-four relapsed or refractory patients were treated with a dose-escalating regimen of oral CC-4047. Clinical responses and adverse effects were identified, and peripheral T-cell subsets, serum cytokines, and proangiogenic factors were evaluated. RESULTS CC-4047 was tolerated with no serious nonhematologic adverse events. All patients were eligible for analysis. Toxicity criteria during the initial 4 weeks of study were used to define the maximum-tolerated dose (MTD). During this period, one patient withdrew with a deep vein thrombosis (DVT) probably caused by an undiagnosed primary melanoma with lymphadenopathy in the groin, one patient withdrew because of progressive disease (PD), and three patients discontinued with neutropenia. Nineteen of 24 patients continued on treatment beyond 4 weeks to PD or development of a serious adverse event. Three further patients developed a DVT at 4, 9, and 11 months. Treatment resulted in a greater than 25% reduction in paraprotein in 67% of patients, 13 patients (54%) experienced a greater than 50% reduction in paraprotein, and four (17%) of 24 patients entered complete remission. The MTD was 2 mg/d. All patients showed increased CD45RO expression on CD4(+) and CD8(+) cells, with a concomitant decrease in CD45RA(+) cells. CC-4047 treatment was associated with significantly increased serum interleukin (IL)-2 receptor and IL-12 levels, which is consistent with activation of T cells and monocytes and macrophages. CONCLUSION This study demonstrates the safety and efficacy of CC-4047. The MTD of CC-4047 orally was 2 mg/d. This is the first report demonstrating in vivo T-cell costimulation by this class of compound, supporting a potential role for CC-4047 as an immunostimulatory adjuvant treatment.
This paper references
10.1097/00001622-200211000-00008
Thalidomide and immunomodulatory drugs as cancer therapy.
N. Raje (2002)
10.1080/1024533021000037199
Thalidomide in the Management of Multiple Myeloma
S. Schey (2002)
10.1038/sj.bjc.6600607
Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects
K. Dredge (2002)
10.1038/sj.onc.1204623
The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications
T. Hideshima (2001)
Antitumor effect of CD40 ligand: elicitation of local and systemic antitumor responses by IL-12 and B7.
A. Nakajima (1998)
10.1182/BLOOD-2002-10-3257
Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis.
N. Giuliani (2003)
10.1046/j.1365-2141.2001.03142.x
Response to thalidomide in progressive multiple myeloma is not mediated by inhibition of angiogenic cytokine secretion
K. Neben (2001)
10.1517/14712598.1.4.675
Immunotherapeutic and antitumour potential of thalidomide analogues
J. Marriott (2001)
10.1007/978-1-4612-4380-9_25
Nonparametric Estimation from Incomplete Observations
E. L. Kaplan (1958)
10.1182/BLOOD.V91.7.2459.2459_2459_2466
Idiotype immunization combined with granulocyte-macrophage colony-stimulating factor in myeloma patients induced type I, major histocompatibility complex-restricted, CD8- and CD4-specific T-cell responses.
A. Osterborg (1998)
10.1084/JEM.187.11.1885
Thalidomide Costimulates Primary Human T Lymphocytes, Preferentially Inducing Proliferation, Cytokine Production, and Cytotoxic Responses in the CD8+ Subset
P. A. Haslett (1998)
10.1056/NEJM199911183412102
Antitumor activity of thalidomide in refractory multiple myeloma.
S. Singhal (1999)
10.1182/BLOOD-2002-06-1925
Idiotype vaccination in multiple myeloma induced a reduction of circulating clonal tumor B cells.
T. Rasmussen (2003)
10.1046/j.1365-2249.2002.01954.x
Thalidomide and its analogues have distinct and opposing effects on TNF‐α and TNFR2 during co‐stimulation of both CD4+ and CD8+ T cells
J. Marriott (2002)
10.1016/S0145-2126(03)00027-4
An UK myeloma forum phase II study of thalidomide; long term follow-up and recommendations for treatment.
S. Schey (2003)
10.1182/BLOOD-2001-12-0245
Thromboembolic events during treatment with thalidomide.
E. Urbauer (2002)
10.3816/CLM.2003.N.011
Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival.
M. Zangari (2003)
10.1073/PNAS.91.9.4082
Thalidomide is an inhibitor of angiogenesis.
R. D'Amato (1994)
10.1182/BLOOD-2002-03-0996
Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma.
P. Richardson (2002)
10.1182/BLOOD.V86.8.3043.BLOODJOURNAL8683043
Idiotype-reactive T-cell subsets and tumor load in monoclonal gammopathies.
Q. Yi (1995)
10.1016/0162-3109(95)00050-X
Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade.
H. Geitz (1996)
10.1172/JCI3861
Characterization of a novel subset of CD8(+) T cells that expands in patients receiving interleukin-12.
J. Gollob (1998)
10.1056/NEJMOA030288
A phase 2 study of bortezomib in relapsed, refractory myeloma.
P. Richardson (2003)
10.1084/JEM.178.4.1223
Antitumor and antimetastatic activity of interleukin 12 against murine tumors
M. Brunda (1993)
10.1084/JEM.177.6.1675
Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation
A. Moreira (1993)
10.1111/j.1365-2249.1995.tb05527.x
The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen‐ and antigen‐stimulated human peripheral blood mononuclear cell cultures
S. M. McHugh (1995)
10.1097/00001813-200306000-00001
Thalidomide analogs as emerging anti-cancer drugs
K. Dredge (2003)
Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.
L. Corral (1999)
10.1016/S1359-6349(03)00006-5
Myeloma: new insights
S. Schey (2003)
10.1016/S0037-1963(01)90017-4
Thalidomide in the management of multiple myeloma.
B. Barlogie (2001)
10.1172/JCI1555
Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis.
C. Coughlin (1998)
10.1046/j.1365-2249.2001.01582.x
Deregulated cytokine network and defective Th1 immune response in multiple myeloma
M. Frassanito (2001)
10.4049/jimmunol.168.10.4914
Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity1
K. Dredge (2002)



This paper is referenced by
10.1007/978-1-4614-8520-9_14
Management of Treatment Complications and Supportive Care
Francis K Buadi (2010)
10.1179/102453312X13336169156294
Novel therapies in monoclonal gammopathies
Rubén Niesvizky (2012)
10.1016/j.leukres.2013.07.007
Modest activity of pomalidomide in patients with myelofibrosis and significant anemia.
N. Daver (2013)
Множественная миелома (лечение рецидивов и рефрактерных форм): обзор литературы и собственные данные. Часть III
Stanislav S. Bessmeltsev (2014)
10.1016/J.BMCL.2007.01.088
Inhibitors of NF-κB derived from thalidomide
E. J. C. de-Blanco (2007)
Cardiotoxicity of Non-Cardiovascular Drugs
G. Minotti (2010)
10.1016/j.ejca.2010.09.002
A phase I, dose-escalation study of pomalidomide (CC-4047) in combination with gemcitabine in metastatic pancreas cancer.
J. Infante (2011)
10.1517/13543784.2011.575060
How to treat patients with relapsed/refractory multiple myeloma: evidence-based information and opinions
M. Offidani (2011)
10.1016/j.clml.2014.06.016
Novel drug combinations for the management of relapsed/refractory multiple myeloma.
S. Usmani (2014)
10.1179/1973947814Y.0000000201
Impact of pomalidomide therapy in multiple myeloma: a recent survey
A. Kumar (2014)
10.1080/10428190802005191
Thalidomide and lenalidomide: Mechanism-based potential drug combinations
S. Vallet (2008)
10.1007/s00109-016-1450-z
The molecular mechanism of thalidomide analogs in hematologic malignancies
Stefanie Lindner (2016)
Absorption, metabolism and excretion of ( 14 C)pomalidomide in humans following oral administration
Matthew HoffmannClaudia (2013)
10.1517/14740338.2016.1154039
The safety of pomalidomide for the treatment of multiple myeloma
J. Jones (2016)
10.1111/bjh.12008
Single‐agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences
H. E. Eve (2012)
10.1188/05.ONF.E127-E138
The changing treatment paradigm in patients with newly diagnosed multiple myeloma: implications for nursing.
J. Tariman (2005)
10.1142/S0219836304000470
Angiogenesis in multiple myeloma: Implications in myeloma therapy
S. Martin (2004)
10.2174/157339507779802151
Myeloma Cells and Their Interactions With the Bone Marrow Endothelial Cells
E. D. Bruyne (2007)
10.1016/J.UCT.2009.03.003
Immunomodulatory agents in oncology
T. Zimmerman (2009)
10.1038/leu.2008.259
Bone marrow microenvironment and the identification of new targets for myeloma therapy
K. Podar (2009)
10.1016/j.ctrv.2011.05.004
Immune modulatory agents in hematopoietic malignancies.
Irina S Idler (2011)
10.1007/978-1-4614-4660-6_3
Cap-Dependent Protein Translation Initiation in Multiple Myeloma: An Attractive Target for Therapy
Shirong Li (2013)
10.21320/2500-2139-2017-10-3-372-380
Pomalidomide in Combination with Low-Dose Dexamethasone as the Treatment of “Double Refractory” Multiple Myeloma
A. Petrov (2017)
10.1016/S1016-3190(08)60034-8
Thalidomide and Its Analogs as Anticancer Agents
Y. Huang (2008)
10.1007/978-3-540-33177-3_43
Thalidomide in multiple myeloma.
T. Moehler (2006)
10.4161/hv.27380
Immunotherapeutic approaches to treat multiple myeloma
M. W. Roeven (2014)
10.1002/ajh.21598
Phase1/‐2 study of Pomalidomide in myelofibrosis
R. Mesa (2010)
10.1586/erp.10.19
Cost–effectiveness of lenalidomide in multiple myeloma
Steve A. Schey (2010)
Current challenges in the management of patients with relapsed/refractory multiple myeloma.
Jesús F. San Miguel (2011)
10.1111/cas.12772
Pomalidomide alone or in combination with dexamethasone in Japanese patients with refractory or relapsed and refractory multiple myeloma
K. Matsue (2015)
10.1182/blood-2012-02-413161
Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis.
A. Dispenzieri (2012)
signaling and platelet function 3 β IIb α integrin The tetraspanin superfamily member CD 151 regulates outside-in
D. E. Jackson (2004)
See more
Semantic Scholar Logo Some data provided by SemanticScholar