Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults

Pierre A Robe, Didier H Martin, Minh T Nguyen-Khac, Maria Artesi, Manuel Deprez, Adelin Albert, Sophie Vanbelle, Stephane Califice, Markus Bredel, Vincent Bours, Pierre A Robe, Didier H Martin, Minh T Nguyen-Khac, Maria Artesi, Manuel Deprez, Adelin Albert, Sophie Vanbelle, Stephane Califice, Markus Bredel, Vincent Bours

Abstract

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.

Figures

Figure 1
Figure 1
Sulfaslazine-associated peritumor oedema. T2 MRI scans obtained at inclusion, prior to Sulfasalazine treatment in patient #4, and 8 days after the initiation of sulfaslaazine treatment (6 g/day). The images demonstrate an increased peritumoral oedema and the developing midline shift. This patient alo developed severe headaches and withdrew from the study.
Figure 2
Figure 2
Tumor growth during Sulfasalazine treatment. A/Tumor growth between inclusion and sulfasalazine treatment arrest (volumes are provided in ml and were measured by segmentation on gadolinium-enhanced T1 MRI scans); B/Gadolinium-enhanced T1 MRI scans of patient #05 at the time of inclusion and after 32 days of sulfasalzine treatment (6 g/day). The tumor volume has more than tripled over this period.
Figure 3
Figure 3
PFS and overasll survival of ISRCTN45828668. Kaplan-Meier estimates of the PFS and overall survival of the patients from the time of inclusion in ISRCTN45828668.

References

    1. Stupp R, Mason WP, Bent MJ van den, 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. doi: 10.1056/NEJMoa043330.
    1. 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. doi: 10.1158/1078-0432.CCR-03-0392.
    1. 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. doi: 10.1006/bbrc.1998.8741.
    1. 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.
    1. Bours V, Bentires-Alj M, Hellin AC, Viatour P, Robe P, Delhalle S, Benoit V, Merville MP. Nuclear factor-kappa B, cancer, and apoptosis. Biochem Pharmacol. 2000;60(8):1085–1089. doi: 10.1016/S0006-2952(00)00391-9.
    1. 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. doi: 10.2176/nmc.41.187.
    1. 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. doi: 10.3171/jns.2002.96.5.0909.
    1. 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. doi: 10.1038/labinvest.3700123.
    1. 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. doi: 10.1007/s11060-004-5757-1.
    1. 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. doi: 10.1007/s10014-005-0186-1.
    1. 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. doi: 10.1038/sj.onc.1202541.
    1. 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.
    1. 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. doi: 10.1200/JCO.2005.02.9405.
    1. 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. doi: 10.1172/JCI992.
    1. 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. doi: 10.1523/JNEUROSCI.5258-04.2005.
    1. 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. doi: 10.1002/jcp.21366.
    1. 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. doi: 10.2165/00003495-199550010-00009.
    1. 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. doi: 10.1186/1471-2407-6-29.
    1. 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. doi: 10.1215/S1152851705000554.
    1. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8(7):1277–1280.
    1. 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.
    1. 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. doi: 10.2353/jmoldx.2008.070169.
    1. 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. doi: 10.2169/internalmedicine.45.1666.
    1. Mut SE, Kutlu G, Ucler S, Erdal A, Inan LE. Reversible encephalopathy due to sulfasalazine. Clin Neuropharmacol. 2008;31(6):368–371. doi: 10.1097/WNF.0b013e31817f125d.
    1. Schoonjans R, Mast A, Abeele G Van den, 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.
    1. Sevgi E, Yalcin G, Kansu T, Varli K. Drug induced intracranial hypertension associated with sulphasalazine treatment. Headache. 2008;48(2):296–298.
    1. 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. doi: 10.1016/0165-5728(91)90120-V.
    1. Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability. Physiol Rev. 2006;86(1):279–367. doi: 10.1152/physrev.00012.2005.
    1. 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. doi: 10.1016/S0006-8993(98)00634-9.
    1. 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. doi: 10.1056/NEJMoa043331.
    1. 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. doi: 10.1158/1541-7786.MCR-07-0280.
    1. 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. doi: 10.1172/JCI1554.
    1. 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. doi: 10.1016/0168-0102(92)90030-G.
    1. 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. doi: 10.1016/j.bcp.2006.07.023.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅