Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects.
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.
Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA.|Department of Immunology of Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.
Taolin
T
Yi
Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA.
Paul
P
Elson
Hitachi Chemical Research Center, Inc., Irvine, CA, USA.
Masato
M
Mitsuhashi
Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA.
Barbara
B
Jacobs
Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA.
Emese
E
Hollovary
Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA.
G Thomas
GT
Budd
Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA.
Timothy
T
Spiro
Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA.
Pierre
P
Triozzi
Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA.
Ernest C
EC
Borden
D000328:Adult; D000368:Aged; D000967:Antimony Sodium Gluconate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003606:Dacarbazine / Q000494:pharmacology; D004359:Drug Therapy, Combination / Q000009:adverse effects* / Q000379:methods*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000097:blood; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012509:Sarcoma / Q000188:drug therapy; D014747:Vinblastine / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D014747:Vinblastine; D003606:Dacarbazine; D010744:Phosphoric Monoester Hydrolases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D002945:Cisplatin; D000967:Antimony Sodium Gluconate