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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: SB-485232
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SB-485232+Rituximab<br>Rituximab 375 milligrams per square meter (mg/m^2) will be administered to subjects with CD20+ B cell lymphoma by intravenous (IV) infusion once a week for four consecutive weeks on Day 1 of Weeks 1 to 4. SB-485232 will be administered by IV infusion over a 2 hour period, at doses ranging from 1 microgram (μg)/kilogram (kg) to 100 μg/kg. SB-485232 will be given once a week for 12 consecutive weeks on Day 2 of Weeks 1 to 4 and Day 2 (± 1 day) of Weeks 5 to 12. SB-485232 will be infused at least 24 hours after the Rituximab infusion was started. | Drug: SB-485232<br>* 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.<br>Drug: Rituximab<br>* Rituximab 375 mg/m^2 will be administered by IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety/tolerability of combination treatment for 4 weeks safety/tolerability of SB-485232 for additional 8 weeks |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Activated NK cells (CD16+/CD56+/CD3-/CD69+/FasL+ or IL-18Ra+) |  | 12 weeks | 
| 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 | 
| CD16 (FcγRIIIA) 158V/F genotyping |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituximab,, oncology, IL-18,, combination study,, cytokine,