Lymphoma, Non-Hodgkin
Conditions
Keywords
Rituximab,, oncology, IL-18,, combination study,, cytokine,
Brief 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.
Interventions
DRUGSB-485232
SB-485232 for injection, 7 mg/vial, will be available as a lyophilized cake. It will be reconstituted with 1.4 mL of water for injection. Each vial of this drug product is a clear, colorless solution containing 5 mg/mL of SB-485232.
DRUGRituximab
Rituximab 375 mg/m\^2 will be administered by IV infusion.
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| safety/tolerability of combination treatment for 4 weeks safety/tolerability of SB-485232 for additional 8 weeks | 12 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Activated cytolytic T cells (CD8+/CD4-/CD3+/CD69+ FasL+ or IL- 18Ra+) | 12 weeks |
| Activated B cells (CD19+/CD25-/CD3-/CD69+) | 12 weeks |
| Activated Neutrophils/Monocytes (CD11b+/CD16+/CD64+/CD14+/CD45+/CD69+) | 12 weeks |
| Regulatory T-cells (FoxP3+/CD25+/CD4+/CD127+) | 12 weeks |
| Immunogenicity (anti-SB-485232 and anti-Rituximab antibodies) | 12 weeks |
| Anti-tumor activity (Radiographic tumor assessments) | 12 weeks |
| Activated NK cells (CD16+/CD56+/CD3-/CD69+/FasL+ or IL-18Ra+) | 12 weeks |
| assess blood values of combination treatment for 4 weeks assess blood values of SB-485232 for additional 8 weeks | 12 weeks |
| Pharmacokinetic parameters for SB-485232 and Rituxan: AUCtau, Cmax, and Cmin. | 12 weeks |
| Pharmacodynamic biomarker responses: | 12 weeks |
| Plasma IFN-γ, GMCSF, IP-10, MIG, and MCP-1 changes | from baseline and predose |
| Plasma IL-18BP change | from baseline |
| PBMC phenotype changes | from baseline and pre-dose |
| CD16 (FcγRIIIA) 158V/F genotyping | 12 weeks |
Countries
United States
Outcome results
None listed