TY - JOUR
T1 - Phase I dose escalation study of sodium stibogluconate (SSG), a protein tyrosine phosphatase inhibitor, combined with interferon alpha for patients with solid tumors
AU - Naing, Aung
AU - Reuben, James M.
AU - Camacho, Luis H.
AU - Gao, Hui
AU - Lee, Bang Ning
AU - Cohen, Evan N.
AU - Verschraegen, Claire
AU - Stephen, Saneese
AU - Aaron, Joann
AU - Hong, David
AU - Wheler, Jennifer
AU - Kurzrock, Razelle
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Cancer
KW - Immunity
KW - Interferon alpha
KW - Phase 1
KW - Sodium stibogluconate
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U2 - 10.7150/jca.2.81
DO - 10.7150/jca.2.81
M3 - Article
C2 - 21326629
AN - SCOPUS:80052015381
SN - 1837-9664
VL - 2
SP - 81
EP - 89
JO - Journal of Cancer
JF - Journal of Cancer
IS - 1
ER -