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

Abstract

Purpose: Sodium stibogluconate (SSG), a small molecule inhibitor of protein tyrosine phosphatases, combined with IFN-alpha-2b (IFN-α) inhibited solid tumor cell line growth in vitro. We conducted a phase I clinical trial with SSG plus IFN-α in advanced cancer patients to assess tolerance, maximum tolerated dose (MTD) and immune system effects.Experimental Design: SSG was administered intravenously alone for five days of week 1, cycle 1 (21 days per cycle) and together with IFN-α 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.Results: 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/m2 SSG and IFN-α, 3 million units TIW. At this dose, patients had a significantly lower number of regulatory T cells (TR Cells) (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-α (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.Conclusions: SSG in combination with IFN-α 2b was well tolerated and augmented cellular immune parameters.

Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects

“…With appropriate assessment for adverse events, future investigations might consider utilizing doses of 1200 mg/m 2 of SSG intravenously for up to 10d in combination with IFNalpha2b with or without chemotherapy. Similar to our findings of acceptable tolerance of SSG in combination with IFN-alpha2b in cancer patients were findings in a concomitant study of similar design [33]. Both trials found that Phase II investigation of SSG could safely utilize doses > 800 and potentially 1200 mg/m 2 for up to 10d in combination with IFN-alpha2b and, based upon our results, with addition of chemotherapy.…”

“…Despite what may have been limitations in assay methodologies for detecting labile phosphor-proteins, a suggestion that prolonged phosphoryation of T and NK cell signaling proteins inhibited by phosphatases may have resulted (Fig 1). In the parallel study patients receiving the higher doses (≥900 mg/m 2 ) of SSG had a significantly lower number of Treg cells and myeloid dendritic cells together with a higher percentage of natural killer (NK) cells that synthesized perforin and of plasmacytoid dendritic cells (pDC) that secreted IFN-gamma in response to activation [33]. These findings suggest that in humans in addition to mice, SSG can have modulatory activity influencing innate and acquired immunity.…”

SHP-1 phosphatase activity counteracts increased T cell receptor affinity

“…Consequently, antibodies against PD-1 and PD-L1 have entered phase 1 clinical trials, and initial results showing objective tumor regression are highly promising (44,45). More recently, 2 phase 1 trials using the phosphatase inhibitor SSG in combination with IFN-α2b have demonstrated safety and targeted inhibition in cancer patients (24,25). Our findings highlight the critical role of SHP-1 expression among the whole panel of engineered CD8 + T cells.…”

“…Sodium stibogluconate (SSG) is widely used to treat visceral leishmaniasis and was recently identified as an important clinically suitable protein tyrosine phosphatase inhibitor in cancer patients (24,25). Notably, SSG has been shown to selectively inhibit protein tyrosine phosphatases, among which SHP-1 was the most sensitive (26).…”

Finding melanoma drugs through a probabilistic knowledge graph

“…Topotecan (Kraut et al, 1997), and Sodium stibogluconate (Naing, 2011) are all drugs in clinical trial that we identified as potential therapies. Many other drugs were identified that are being studied in the lab.…”