A Phase I, Dose-Escalation Study to Assess the Safety and Biological Activity of Recombinant Human Interleukin-18
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: SB-485232+Rituximab 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
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.
Drug: Rituximab
Rituximab 375 mg/m^2 will be administered by IV infusion.
|
Outcome Measures
Primary Outcome Measures
- safety/tolerability of combination treatment for 4 weeks safety/tolerability of SB-485232 for additional 8 weeks [12 weeks]
Secondary Outcome Measures
- 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
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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.
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Prior treatment with Rituximab is allowed, provided it was completed at least six months before study enrollment.
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Male or female ≥ 18 years of age.
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Measurable or evaluable disease.
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Predicted life expectancy of at least 12 weeks.
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ECOG Performance Status of 0 or 1.
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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.
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A signed and dated written informed consent form is obtained from the subject.
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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:
- non-childbearing potential (i.e., physiologically incapable of becoming pregnant) including any female who:
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has had a hysterectomy,
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has had a bilateral oophorectomy (ovariectomy),
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has had a bilateral tubal ligation,
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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:
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any intrauterine device (IUD) with a documented failure rate of less than
1% per year.
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vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female.
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oral contraceptive (either combined or progesterone only).
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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.
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Adequate organ function,
Exclusion Criteria:
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Women who are pregnant or are breast-feeding.
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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.
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The subject has diabetes mellitus with poor glycemic control.
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The subject has a history of human immunodeficiency virus (HIV) or other immunodeficiency disease.
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The subject has positive Hepatitis B surface antigen.
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Corrected QT interval (QTc) > 480msec.
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The subject has a history of a severe infusion related reaction or tumor lysis syndrome following treatment with Rituximab (Section 10.2.2).
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The subject has a circulating malignant cell count > 25,000/mm3 in peripheral blood.
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The subject has known anaphylaxis or IgE-mediated hypersensitivity to murine proteins.
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The subject has an acute infection or severe or uncontrolled infections requiring systemic antibiotic therapy.
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Any serious medical or psychiatric disorder that would interfere with subject safety or informed consent.
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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.
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Receiving concurrent chemotherapy, immunotherapy, radiotherapy, or investigational therapy.
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Oral corticosteroids within 14 days of study entry.
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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).
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History of ventricular arrhythmias requiring drug or device therapy.
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Any unresolved or unstable serious toxicity from prior administration of another investigational drug.
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Any investigational drug within 30 days or five half-lives (whichever is longer) preceding the first dose of SB-485232.
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Donation of blood in excess of 500 mL within a 56-day period prior to dosing.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | GSK Investigational Site | Chicago | Illinois | United States | 60637 |
| 2 | GSK Investigational Site | Indianapolis | Indiana | United States | 46202 |
Sponsors and Collaborators
- GlaxoSmithKline
Investigators
- Study Director: GSK Clinical Trials, GlaxoSmithKline
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- ILI105618