a phase i, dose-escalation study to assess the safety and biological activity of recombinant human interleukin-18

Conditions: Lymphoma, Non-Hodgkin

Summary: the purpose is to identify a dose of sb-485232 which is safe, tolerable and effective when used in combination with rituximab in patients with non-hodgkin's lymphoma (nhl). this study will use a standard treatment regimen of rituximab in combination with rising doses of sb-485232. the dose selected from this study will be used in a future studies.


Eligibility criteria:
inclusion criteria: * histologically confirmed diagnosis of any subtype of cd20+ b cell nhl. subjects must have disease that progressed after standard therapy or for which there is no effective standard therapy (including high-dose therapy and autologous stem cell transplantation). note: if the subject has had a prior autologous stem cell transplant, it must have occurred at least three months prior to screening and the subject must be fully recovered from any acute toxicities. * prior treatment with rituximab is allowed, provided it was completed at least six months before study enrollment. * male or female ≥ 18 years of age. * measurable or evaluable disease. * predicted life expectancy of at least 12 weeks. * ecog performance status of 0 or 1. * no chemotherapy, immunotherapy, hormonal therapy, or biological therapy for cancer, radiotherapy, or surgical procedures (except for minor surgical procedures) within four weeks before beginning treatment with sb-485232 (6 weeks for nitrosoureas and mitomycin c). subjects must have recovered from toxicities (incurred as a result of previous therapy) sufficiently to be entered into a phase i study. * a signed and dated written informed consent form is obtained from the subject. * the subject is able to understand and comply with protocol requirements, timetables, instructions and protocol-stated restrictions. the subject is likely to maintain good venous blood access for pk and pd sampling throughout the study. * a female is eligible to enter and participate in the study if she is of: a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant) including any female who: * has had a hysterectomy, * has had a bilateral oophorectomy (ovariectomy), * has had a bilateral tubal ligation, * is post-menopausal (demonstrate total cessation of menses for greater than 1year), if amenorrheic for less than one year, post-menopausal status will be confirmed by serum follicle stimulating hormone (fsh) and oestradiol concentrations at screening. or, b. childbearing potential, has a negative serum pregnancy test at the screen visit, and agrees to one of the following gsk acceptable contraceptive methods: * any intrauterine device (iud) with a documented failure rate of less than 1% per year. * vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female. * oral contraceptive (either combined or progesterone only). * because of the unacceptable failure rate of barrier (chemical and/or physical) methods, the barrier method of contraception must only be used in combination with other acceptable methods described above. * adequate organ function, exclusion criteria: * women who are pregnant or are breast-feeding. * significant cardiac, pulmonary, metabolic, renal, hepatic, gastrointestinal or autoimmune conditions that in the opinion of the investigator and/or gsk medical monitor, places the subject at an unacceptable risk as participant in this trial. * the subject has diabetes mellitus with poor glycemic control. * the subject has a history of human immunodeficiency virus (hiv) or other immunodeficiency disease. * the subject has positive hepatitis b surface antigen. * corrected qt interval (qtc) \> 480msec. * the subject has a history of a severe infusion related reaction or tumor lysis syndrome following treatment with rituximab (section 10.2.2). * the subject has a circulating malignant cell count \> 25,000/mm3 in peripheral blood. * the subject has known anaphylaxis or ige-mediated hypersensitivity to murine proteins. * the subject has an acute infection or severe or uncontrolled infections requiring systemic antibiotic therapy. * any serious medical or psychiatric disorder that would interfere with subject safety or informed consent. * known leptomeningeal disease or evidence of prior or current metastatic brain disease. routine screening with central nervous system (cns) imaging studies (ct or mri) is required only if clinically indicated. * receiving concurrent chemotherapy, immunotherapy, radiotherapy, or investigational therapy. * oral corticosteroids within 14 days of study entry. * history of alcohol abuse within six months of screening or alcohol consumption in the past six months exceeding seven drinks/week for women and 14 drinks/week for men (where 1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor). * history of ventricular arrhythmias requiring drug or device therapy. * any unresolved or unstable serious toxicity from prior administration of another investigational drug. * any investigational drug within 30 days or five half-lives (whichever is longer) preceding the first dose of sb-485232. * donation of blood in excess of 500 ml within a 56-day period prior to dosing.

Keywords: rituximab, oncology il-18, combination study, cytokine,