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].
[en] BACKGROUND: The prognosis of patients suffering from WHO grade 3 and 4 astrocytic glioma remains poor despite surgery, radiation therapy and the use of current chemotherapy regimen. Indeed, the median survival of glioblastoma multiforme (WHO grade 4) patients is at best 14.6 month with only 26.5 percent of the patients still alive after 2 years and the median survival of anaplastic astrocytomas (WHO grade 3) is 19.2 month. Recent evidence suggests that the transcription factor NF-kappaB is constitutively expressed in malignant gliomas and that its inhibition by drugs like Sulfasalazine may block the growth of astrocytic tumors in vitro and in experimental models of malignant gliomas. DESIGN: ULg_GBM_04/1 is a prospective, randomized, double blind single-center phase 1-2 study. A total of twenty patients with progressive malignant glioma despite surgery, radiation therapy and a first line of chemotherapy will be recruited and assigned to four dosage regimen of Sulfasalazine. This medication will be taken orally t.i.d. at a daily dose of 1.5-3-4 or 6 g, continuously until complete remission, evidence of progression or drug intolerance. Primary endpoints are drug safety in the setting of malignant gliomas and tumor response as measured according to MacDonald's criteria. An interim analysis of drug safety will be conducted after the inclusion of ten patients. The complete evaluation of primary endpoints will be conducted two years after the enrollment of the last patient or after the death of the last patient should this occur prematurely. DISCUSSION: The aim of this study is to evaluate the safety and efficacy of Sulfasalazine as a treatment for recurring malignant gliomas. The safety and efficacy of this drug are analyzed as primary endpoints. Overall survival and progression-free survival are secondary endpoint.
Disciplines :
Surgery
Author, co-author :
Robe, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine - Département des sciences biomédicales et précliniques
Martin, Didier ; Centre Hospitalier Universitaire de Liège - CHU > Neurochirurgie
Albert, Adelin ; Université de Liège - ULiège > Département des sciences de la santé publique > Informatique médicale et biostatistique - Département de mathématique
Deprez, Manuel ; Université de Liège - ULiège > Département des sciences cliniques > Neuropathologie
Chariot, Alain ; Centre Hospitalier Universitaire de Liège - CHU > Chimie médicale
Bours, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > Génétique
Language :
English
Title :
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].
Black PM, Alexander E, Martin C, Moriarty T, Nabavi A, Wong TZ, Schwartz RB, Jolesz F: Craniotomy for tumor treatment in an intraolperative magnetic resonance imaging unit. Neurosurgery 1999, 45(3):423-31; discussion 431-3.
Shrieve DC, Alexander E, Black PM, Wen PY, Fine HA, Kooy HM, Loeffler JS: Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome. J Neurosurg 1999, 90(1):72-77.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO: Radiotherapy plus concomitant and adjuvant temozolomidle for glioblastoma. N Engl J Med 2005, 352(10):987-996.
Ohgaki H, Kleihues P: Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oilgodendroglial gliomas. J Neuropothol Exp Neural 2005, 64(6):479-489.
Ansari SA, Safak M, Del Valle L, Enam S, Amini S, Khalili K; Cell cycle regulation of NF-kappa b-binding activity in cells from human glioblastomas. Exp Cell Res 2001, 265(2):221-233.
Robe PA, Bentires-Alj M, Bonif M, Rogister B, Deprez M, Haddada H, Khac MT, Jolois O, Erkmen K, Merville MIP, Black PM, Bours V: In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clin Cancer Res 2004, 10(16):5595-5603.
Yin D, Zhou H, Kumagai T, Liu G, Ong JM, Black KL, Koeffler HP: Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastorna multiforme (GBM). Oncogene 2005, 24(3):344-354.
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 glionnas. Lob Invest 2004, 84(8):941-951.
Bentires-Alj M, Barbu V, Fillet M, Chariot A, Relic B, Jacobs N, Gielen J, Merville MP, Bours V: NF-kappaB transcription factor induces drug resistance through MDRI expression in cancer cells. Oncogene 2003, 22(1):90-97.
Rayet B, Gelinas C: Aberrant rel/nfkb genes and activity in human cancer. Oncogene 1999, 18(49):6938-6947.
Anderson KC: Moving disease biology from the laboratory to the clinic. Semin Oncol 2002, 29(6 Suppi 17):17-20.
Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade: U.S. FDA approval for theent of multiple myeloma progressing on prior therapy. Oncologist 2003, 8(6):508-513.
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.
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.
Weber CK, Liptay S, Wirth T, Adler G, Schmid RM: Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology 2000, 119(5): 1209-1218.
