Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults.
[en] BACKGROUND: Sulfasalazine, a NF-kappaB and x(c)-cystine/glutamate antiport inhibitor, has demonstrated a strong antitumoral potential in preclinical models of malignant gliomas. As it presents an excellent safety profile, we initiated a phase 1/2 clinical study of this anti-inflammatory drug for the treatment of recurrent WHO grade 3 and 4 astrocytic gliomas in adults. METHODS: 10 patients with advanced recurrent anaplastic astrocytoma (n = 2) or glioblastoma (n = 8) aged 32-62 years were recruited prior to the planned interim analysis of the study. Subjects were randomly assigned to daily doses of 1.5, 3, 4.5, or 6 grams of oral sulfasalazine, and treated until clinical or radiological evidence of disease progression or the development of serious or unbearable side effects. Primary endpoints were the evaluation of toxicities according to the CTCAE v.3.0, and the observation of radiological tumor responses based on MacDonald criteria. RESULTS: No clinical response was observed. One tumor remained stable for 2 months with sulfasalazine treatment, at the lowest daily dose of the drug. The median progression-free survival was 32 days. Side effects were common, as all patients developed grade 1-3 adverse events (mean: 7.2/patient), four patients developed grade 4 toxicity. Two patients died while on treatment or shortly after its discontinuation. CONCLUSION: Although the proper influence of sulfasalazine treatment on patient outcome was difficult to ascertain in these debilitated patients with a large tumor burden (median KPS = 50), ISRCTN45828668 was terminated after its interim analysis. This study urges to exert cautiousness in future trials of Sulfasalazine for the treatment of malignant gliomas. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45828668.
Disciplines :
Genetics & genetic processes
Author, co-author :
Robe, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique générale et humaine - Département des sciences biomédicales et précliniques
Martin, Didier ; Centre Hospitalier Universitaire de Liège - CHU > Neurochirurgie
Nguyen-Khac, Minh-Tuan ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
Artesi, Maria ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique générale et humaine
Deprez, Manuel ; Université de Liège - ULiège > Département des sciences cliniques > Neuropathologie
Albert, Adelin ; Université de Liège - ULiège > Département des sciences de la santé publique > Informatique médicale et biostatistique - Département de mathématique
Vanbelle, Sophie ; Université de Liège - ULiège > Département des sciences de la santé publique > Département des sciences de la santé publique
Bours, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique générale et humaine
Language :
English
Title :
Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults.
Stupp R, Mason WP, Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005, 352(10):987-996. 10.1056/NEJMoa043330, 15758009.
Robe PA, Bentires-Alj M, Bonif M, Rogister B, Deprez M, Haddada H, Khac MT, Jolois O, Erkmen K, Merville MP. In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clin Cancer Res 2004, 10(16):5595-5603. 10.1158/1078-0432.CCR-03-0392, 15328202.
Basu S, Rosenzweig KR, Youmell M, Price BD. The DNA-dependent protein kinase participates in the activation of NF kappa B following DNA damage. Biochem Biophys Res Commun 1998, 247(1):79-83. 10.1006/bbrc.1998.8741, 9636658.
Manna SK, Aggarwal BB. Alpha-melanocyte-stimulating hormone inhibits the nuclear transcription factor NF-kappa B activation induced by various inflammatory agents. J Immunol 1998, 161(6):2873-2880.
Hayashi S, Yamamoto M, Ueno Y, Ikeda K, Ohshima K, Soma G, Fukushima T. Expression of nuclear factor-kappa B, tumor necrosis factor receptor type 1, and c-Myc in human astrocytomas. Neurol Med Chir (Tokyo) 2001, 41(4):187-195. 10.2176/nmc.41.187, 11381677.
Nagai S, Washiyama K, Kurimoto M, Takaku A, Endo S, Kumanishi T. Aberrant nuclear factor-kappaB activity and its participation in the growth of human malignant astrocytoma. J Neurosurg 2002, 96(5):909-917. 10.3171/jns.2002.96.5.0909, 12005399.
Wang H, Wang H, Zhang W, Huang HJ, Liao WS, Fuller GN. Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Invest 2004, 84(8):941-951. 10.1038/labinvest.3700123, 15184909.
Nagai S, Kurimoto M, Washiyama K, Hirashima Y, Kumanishi T, Endo S. Inhibition of cellular proliferation and induction of apoptosis by curcumin in human malignant astrocytoma cell lines. J Neurooncol 2005, 74(2):105-111. 10.1007/s11060-004-5757-1, 16193380.
Tsunoda K, Kitange G, Anda T, Shabani HK, Kaminogo M, Shibata S, Nagata I. Expression of the constitutively activated RelA/NF-kappaB in human astrocytic tumors and the in vitro implication in the regulation of urokinase-type plasminogen activator, migration, and invasion. Brain Tumor Pathol 2005, 22(2):79-87. 10.1007/s10014-005-0186-1, 18095109.
Piret B, Schoonbroodt S, Piette J. The ATM protein is required for sustained activation of NF-kappaB following DNA damage. Oncogene 1999, 18(13):2261-2271. 10.1038/sj.onc.1202541, 10327072.
Robe P, Nguyen-Khack MT, Lambert F, Lechanteur C, Jolois O, Ernst-Gengoux P, Rogister B, Bours V. Sulfasalazine unveils a contact-independent HSV-TK/ganciclovir gene therapy bystnader effect in malignant gliomas. International Journal of Oncology 2007, 30(1):283-90.
Bredel M, Bredel C, Juric D, Duran GE, Yu RX, Harsh GR, Vogel H, Recht LD, Scheck AC, Sikic BI. Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol 2006, 24(2):274-287. 10.1200/JCO.2005.02.9405, 16365179.
Wahl C, Liptay S, Adler G, Schmid RM. Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest 1998, 101(5):1163-1174. 10.1172/JCI992, 508669, 9486988.
Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GY, Sontheimer H. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neurosci 2005, 25(31):7101-7110. 10.1523/JNEUROSCI.5258-04.2005, 2681064, 16079392.
Lo M, Wang YZ, Gout PW. The x(c)-cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol 2008, 215(3):593-602. 10.1002/jcp.21366, 18181196.
Rains CP, Noble S, Faulds D. Sulfasalazine. A review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis. Drugs 1995, 50(1):137-156. 10.2165/00003495-199550010-00009, 7588084.
Robe PA, Martin D, Albert A, Deprez M, Chariot A, Bours V. A phase 1-2, prospective, double blind, randomized study of the safety and efficacy of Sulfasalazine for the treatment of progressing malignant gliomas: study protocol of [ISRCTN45828668]. BMC Cancer 2006, 6(1):29. 10.1186/1471-2407-6-29, 1368982, 16448552.
Chang SM, Reynolds SL, Butowski N, Lamborn KR, Buckner JC, Kaplan RS, Bigner DD. GNOSIS: guidelines for neuro-oncology: standards for investigational studies-reporting of phase 1 and phase 2 clinical trials. Neuro Oncol 2005, 7(4):425-434. 10.1215/S1152851705000554, 1871726, 16212807.
Macdonald DR, Cascino TL, Schold SC, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990, 8(7):1277-1280.
Gering DNA, Kikinis R, Grimson W, Hata N, Everett P, Jolesz F, Wells W. An Integrated Visualization System for Surgical Planning and Guidance using Image Fusion and Interventional Imaging. Int Conf Med Image Comput Comput Assist Interv 1999, 2:11.
Vlassenbroeck I, Califice S, Diserens A, Migliavacca E, Straub J, Di Stefano I, Moreau F, Hamou M, Renard I, Delorenzi M. Validation of Real-Time MSP to Determine MGMT Promoter Methylation in Glioma. J Mol Diagn 2008, 10:6.
Takahashi H, Ito S, Nagumo K, Kojima S, Umibe T, Hattori T. Salazosulfapyridine-induced encephalopathy with symmetrical lesions in the basal ganglia and thalami. Intern Med 2006, 45(15):927-929. 10.2169/internalmedicine.45.1666, 16946577.
Mut SE, Kutlu G, Ucler S, Erdal A, Inan LE. Reversible encephalopathy due to sulfasalazine. Clin Neuropharmacol 2008, 31(6):368-371. 10.1097/WNF.0b013e31817f125d, 19050416.
Schoonjans R, Mast A, Abeele G, Dewilde D, Achten E, Van Maele V, Pauwels W. Sulfasalazine-associated encephalopathy in a patient with Crohn's disease. Am J Gastroenterol 1993, 88(10):1759-1763.
Sevgi E, Yalcin G, Kansu T, Varli K. Drug induced intracranial hypertension associated with sulphasalazine treatment. Headache 2008, 48(2):296-298.
Correale J, Olsson T, Bjork J, Smedegard G, Hojeberg B, Link H. Sulfasalazine aggravates experimental autoimmune encephalomyelitis and causes an increase in the number of autoreactive T cells. J Neuroimmunol 1991, 34(2-3):109-120. 10.1016/0165-5728(91)90120-V, 1680877.
Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability. Physiol Rev 2006, 86(1):279-367. 10.1152/physrev.00012.2005, 16371600.
Hurst RD, Heales SJ, Dobbie MS, Barker JE, Clark JB. Decreased endothelial cell glutathione and increased sensitivity to oxidative stress in an in vitro blood-brain barrier model system. Brain Res 1998, 802(1-2):232-240. 10.1016/S0006-8993(98)00634-9, 9748597.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005, 352(10):997-1003. 10.1056/NEJMoa043331, 15758010.
Li A, Walling J, Kotliarov Y, Center A, Steed ME, Ahn SJ, Rosenblum M, Mikkelsen T, Zenklusen JC, Fine HA. Genomic changes and gene expression profiles reveal that established glioma cell lines are poorly representative of primary human gliomas. Mol Cancer Res 2008, 6(1):21-30. 10.1158/1541-7786.MCR-07-0280, 18184972.
Morabito L, Montesinos MC, Schreibman DM, Balter L, Thompson LF, Resta R, Carlin G, Huie MA, Cronstein BN. Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5'-nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest 1998, 101(2):295-300. 10.1172/JCI1554, 508567, 9435300.
Rathbone MP, Middlemiss PJ, Kim JK, Gysbers JW, DeForge SP, Smith RW, Hughes DW. Adenosine and its nucleotides stimulate proliferation of chick astrocytes and human astrocytoma cells. Neurosci Res 1992, 13(1):1-17. 10.1016/0168-0102(92)90030-G, 1314349.
Olivier S, Robe P, Bours V. Can NF-kappaB be a target for novel and efficient anti-cancer agents?. Biochem Pharmacol 2006, 72(9):1054-68. 10.1016/j.bcp.2006.07.023, 16973133.
