Phase I Dose Escalation Study of Sodium Stibogluconate (SSG), a Protein Tyrosine Phosphatase Inhibitor, Combined with Interferon Alpha for Patients with Solid Tumors

• Main Author: Aung Naing, James M. Reuben, Luis H. Camacho, Hui Gao, Bang-Ning Lee, Evan N. Cohen, Claire Verschraegen, Saneese Stephen, Joann Aaron, David Hong, Jennifer Wheler, Razelle Kurzrock
• Format: Article
• Language: English
• Published: Ivyspring International Publisher 2011-01-01
• Series: Journal of Cancer
• Online Access: http://www.jcancer.org/v02p0081.htm

<p><b>Purpose:</b> Sodium stibogluconate (SSG), a small molecule inhibitor of protein tyrosine phosphatases, combined with IFN-alpha-2b (IFN-&#945;) inhibited solid tumor cell line growth <i>in vitro</i>. We conducted a phase I clinical trial with SSG plus IFN-&#945; in advanced cancer patients to assess tolerance, maximum tolerated dose (MTD) and immune system effects.</p><p><b>Experimental Design:</b> SSG was administered intravenously alone for five days of week 1, cycle 1 (21 days per cycle) and together with IFN-&#945; 2b s (3 million units sc TIW) in week 2, and after a rest during week 3, on a 2-week on/1-week off cycle. SSG dose levels were 400, 600, 900, 1125, and 1350 mg/m².</p><p><b>Results:</b> Twenty-four patients were studied. Common toxicities included asymptomatic elevated serum lipase, thrombocytopenia, fatigue, fever, chills and anemia. The dose-limiting toxicities (DLT) were hypokalemia, thrombocytopenia, fatigue, pancreatitis and skin rash. The MTD was 900 mg/m²SSG and IFN-&#945;, 3 million units TIW. At this dose, patients had a significantly lower number of regulatory T cells (T_RCells) (p = 0.012), myeloid dendritic cells (mDC) (p = 0.028); higher percentage of natural killer (NK) cells that synthesized perforin (p = 0.046) and of plasmacytoid dendritic cells (pDC) that secreted IFN-&#945; (p = 0.018) in response to activation through toll-like receptor (TLR) 7 and TLR 8 by CL097, the highly water-soluble derivative of the imidazoquinoline compound R848.</p><p><b>Conclusions:</b> SSG in combination with IFN-&#945; 2b was well tolerated and augmented cellular immune parameters.</p>