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"
- 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,
- 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
- 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
- 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
- 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
- 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.