Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers

Abstract

We assessed the safety, tolerability and efficacy of the immunomodulatory drug, CC-5013 (REVIMID trade mark ), in the treatment of patients with metastatic malignant melanoma and other advanced cancers. A total of 20 heavily pretreated patients received a dose-escalating regimen of oral CC-5013. Maximal tolerated dose, toxicity and clinical responses were evaluated and analysis of peripheral T-cell surface markers and serum for cytokines and proangiogenic factors were performed. CC-5013 was well tolerated. In all, 87% of adverse effects were classified as grade 1 or grade 2 according to Common Toxicity Criteria and there were no serious adverse events attributable to CC-5013 treatment. Six patients failed to complete the study, three because of disease progression, two withdrew consent and one was entered inappropriately and withdrawn from the study. The remaining 14 patients completed treatment without dose reduction, with one patient achieving partial remission. Evidence of T-cell activation was indicated by significantly increased serum levels of sIL-2 receptor, granulocyte-macrophage colony-stimulating factor, interleukin-12 (IL-12), tumour necrosis factor-alpha and IL-8 in nine patients from whom serum was available. However, levels of proangiogenic factors vascular endothelial growth factor and basic foetal growth factor were not consistently affected. This study demonstrates the safety, tolerability and suggests the clinical activity of CC-5013 in the treatment of refractory malignant melanoma. Furthermore, this is the first report demonstrating T-cell stimulatory activity of this class of compound in patients with advanced cancer.

Figure 1

Evidence of clinical response during CC-5013 treatment. (A) Patient SR9 exhibited extensive nodular cutaneous disease over his left thigh. Following treatment (B) lesions became flattened and attenuated. (C) Patient PB13 shows mediastinal mass (arrowed) on CT scan which is reduced (D) after treatment.

Figure 2

Changes in serum sIL-2 receptor, GM-CSF, TNF-α and IL-12 levels due to CC-5013 treatment. Levels pretreatment (baseline) are compared to levels at follow-up (at 4–5 weeks). sIL-2 receptor; ^*P=0.0005 (baseline vs follow-up). GM-CSF; ^*P=<0.0001. TNF-α; ^*P=0.0056. IL-12; ^*P=0.032.

Figure 3

Detection of proangiogenic factors VEGF, IL-8 and b-FGF in the serum of patients is not significantly changed by CC-5013 treatment compared to baseline. VEGF; NS, P=0.566. IL-8; ^*P=0.047. b-FGF; NS, P=0.427.

Figure 4

Effect of CC-5013 treatment on the CD4+ and CD8+ T-cell surface expression of CD45 isoforms. Data are expressed as percentage expression on cells’ pretreatment (baseline) and at follow-up (4–5 weeks after starting treatment). For CD4+ cells: CD45RA expression; ^*P=0.003. CD45RO expression; NS, P=0.105. For CD8+ cells: CD45RA expression; ^*P=0.049. CD45RO expression; NS, P=0.065.