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

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.

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

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

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.