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

Abstract

Since sodium stibogluconate (SSG) inhibited phosphatases including SHP-1 and augmented anti-tumor actions of IFN-α2b in vitro and in mice, two Phase I trials of SSG/IFN-α2b combination were undertaken to evaluate safety and target inhibition. Escalating doses of SSG (200-1200 mg/m2) and fixed doses of IFN-α2b (3x106 units/m2) with or without chemotherapy (dacarbazine, vinblastine, cisplatin) were evaluated for side effects and impact on SHP-1 phospho-substrates and IFNα-stimulated-genes (ISGs) in peripheral blood in 40 patients with metastatic melanoma, soft tissue sarcomas, gastrointestinal stromal tumors, and breast or colorectal carcinomas who did not have other established treatment options. Common adverse events were bone marrow suppression, fatigue, gastrointestinal upset, and asymptomatic lipase elevation (n=13); the latter was dose related and mostly after 10d of SSG/IFN-α2b in combination. Levels of SHP-1 substrates (pSTAT1, pSTAT3, pLck and pSlp76) were increased (up to 3x) in peripheral blood cells following SSG with no potentiation by combination with IFN-α2b. Representative ISGs in peripheral blood were induced after IFN-α2b at 4 and 24 hrs with selective modulations by combination. The median time on trials was 2.3 months (10-281d) with no objective regression of disease. Alive at 1y were 17/40 (43%) patients and after 2y were 8/40 (20%) following treatment initiation. These data demonstrate that SSG impacted signal molecules consistent with PTP inhibition and was tolerated in combination with IFN-α2b. Phase II investigations of SSG could safely utilize doses of up to 1200 mg/m2 of SSG for up to 10d alone or in combination with IFN-α2b with or without chemotherapy.

Figure 1. SSG modulates peripheral blood cell phospho-proteins in patients

Peripheral blood samples were collected pre- and post-treatments from patients as indicated (A and D). Selective phospho-proteins in the samples were evaluated by SDS-PAGE/Western blotting with antibodies as indicated (B and E). The relative levels of the phospho-proteins were quantified by densitometry (C and F).

Figure 2. Peripheral transcripts levels of selective ISGs in patients

Peripheral blood samples were collected pre- and post-treatments from 4 patients as indicated (A). The relative levels (fold change) of transcripts for STAT1, IRF-7, XAF1 and GIP2 were quantified by quantitative RT-PCR (B-E). Each symbol in panel B-E indicates a different patient.

Figure 3. Peripheral protein levels of selective ISGs in patients

Peripheral blood samples were collected at time points pre- and post-treatments from patients as indicated (A). The relative sera protein levels (ratio) of Beta2 microglobulin, TRAIL, CXCL11 and CCL8 were quantified by ELISA (B-E). Each symbol in panel B-E indicates a different patient.