Abstract
3011 Background: SSG is a potent inhibitor of IFN-α signaling protein tyrosine phosphatases (PTPases). Combination of SSG+IFN alpha-2b inhibits growth of melanoma, myeloma, colon, prostate, and breast carcinoma cell lines in vitro. We designed a dose-finding trial to assess toxicities, MTD, PK, PTPase modulation, and the immune effects of this combination. Methods: A phase I trial testing a 6-week regimen consisting of: (1) IV SSG for 5 days of the first week of cycle (2) IFN α-2b was administered SQ 3 times/wk (tiw) during week (3) Both drugs are given in combination thereafter on a 2 wk-on /1 wk-off schedule. SSG was administered at 5 different dose levels (400; 600; 900; 1,350; 1,125mg/m2). Results: 19 patients (17 patients at MDACC and 2 at UNM) (median patient age =59 yrs, range 33–82) received 31 courses. Diagnoses included; melanoma (5), colorectal (3), pancreas (3), and prostate (1), neuroendocrine (1), adenocystic carcinoma (1), malignant granulosa cell (1), squamous cell carcinoma of head/neck (1), peritoneal mesothelioma (1) and ovarian (1). Common toxicities include fatigue, myalgia, fever, chills, serum elevation of amylase/lipase, leukopenia, and thrombocytopenia. Hypokalemia and rash were dose-limiting toxicities at 1,350 mg/m2. Cmax on Day 8, 30 min post IV administration was (72,428 mcg/L); elimination half-life is 22.5 hours. Significant changes in immune parameters were observed in patients receiving 900 mg of SSG and above. There was a significant decrease in the number of CD4+CD25hi T-regulatory cells (26.6/μL vs 14.0/μL, p = 0.012) and in myeloid DC (3.1/μL vs 1.7/μL, p = 0.028). With respect to function, there was significant increase in %NKC that synthesized perforin (65.9% vs 75.6%, p = 0.046), and an increase in the % plasmacytoid DC that secreted IFN-α (3.2% vs 19.8%, p = 0.018) in response to activation through TLR7/8 by CL097. Conclusions: SSG in combination with IFN was well tolerated. Dose escalation stopped at 1,350 mg/m2. PK data suggest a linear accumulation of SSG with rapid excretion after 120 minutes. Preliminary immune monitoring suggests that the combination of SSG and IFN-α is capable of augmenting cellular immunity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pharmion Pharmion, VioQuest Pharmion, Vioquest
Published Version
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