J. Hwang, S. Park, A. Amin
2004
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0
Influential Citations
6
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Journal
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Abstract
3111 Background: HYB2055 (IMOxine) is a 2nd generation immunomodulatory oligonucleotide (IMO TM) that is thought to activate the innate immune system through the TLR9 receptor. In human cell-based assays, IMOxine has induced Th-1 responses. In nude mouse xenografts with colon, breast, lung cancer, and glioma cell lines, IMOxine showed potent antitumor activity. METHODS IMOxine is a weekly (wk) subcutaneous injection, with 1 cycle being 4 injections. This study is to evaluate 5 Dose Levels (DL: A:0.04; B:0.16; C:0.32; D:0.48; E: 0.64 mg/kg/wk). Pt eligibility criteria are standard for phase I trials. Typical phase I escalation schema is used, with dose escalation if 0/3 or 0-1/6 pt have dose limiting toxicity (DLT). DLT are any grade (gr) 4 toxicity, or any gr 3 non-hematologic toxicity preventing re-treatment for 2 wk. The maximum tolerated dose is the highest DL with 0-1/6 pt with DLT. Plasma is collected for measurement of selected cytokines and for pharmacokinetics of IMOxine. T and B lymphocyte subsets, monocyte/macrophages, dendritic cells, and NK cells are elucidated by flow cytometry. NK cell activity is assayed. RESULTS To 12/15/03, 16 pt (12 male) age 41-82 have been enrolled on 4 DL (A: 3; B:4; C:4; D:5 pts), and have received a total of 136 injections. Group E is open for enrollment. No DLT have occurred. Of 10 pt evaluable after 8 wk of therapy, 6 had stable disease (SD), and 2/4 had SD at 16 wk. One pt with metastatic Hurthle cell carcinoma has SD after 6 months, and continues on therapy. Mild to moderate erythema (typically maximal at 48hr) and induration were noted in 13/16 pts. Mainly gr 1 toxicities have occurred: Fatigue (11); chills or fever (9); myalgia (5); headache (4); abdominal discomfort (3); diarrhea, constipation, anorexia, nausea (2); hypotension (1). Immunopharmacology results at 24hr post injection show transient decreases in circulating lymphocytes and trends of increases in CD69+ and/or CD86+ activated lymphocytes. Circulating B cell percentages increased more gradually. CONCLUSIONS IMOxine has been administered safely through 136 total doses, including a maximum of 25 weekly doses to date in 1 pt. Immunological activity has been demonstrated over the range of doses studied. [Table: see text].