A Phase I, Dose-Escalation Study to Assess the Safety and Biological Activity of Recombinant Human Interleukin-18

A Phase I, Dose-Escalation Study to Assess the Safety and Biological Activity of Recombinant Human Interleukin-18 (SB-485232) Administered by Intravenous Infusion in Combinationwith Rituximab in Adult Patients With B Cell Non-Hodgkin'sLymphoma"

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.

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.