A Phase I, Dose-Escalation Study to Assess the Safety and Biological Activity of Recombinant Human Interleukin-18
This study has been completed.
Information provided by (Responsible Party):
First received: July 10, 2007
Last updated: May 31, 2012
Last verified: October 2011
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.
B Cell Non-Hodgkin's Lymphoma
Drug: interleukin-18, Rituxan, Rituximab
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||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"
Primary Outcome Measures:
- safety/tolerability of combination treatment for 4 weeks safety/tolerability of SB-485232 for additional 8 weeks [ Time Frame: 12 weeks ]
Secondary Outcome Measures:
- assess blood values of combination treatment for 4 weeks assess blood values of SB-485232 for additional 8 weeks [ Time Frame: 12 weeks ]
- Pharmacokinetic parameters for SB-485232 and Rituxan: AUCtau, Cmax, and Cmin. [ Time Frame: 12 weeks ]
- Pharmacodynamic biomarker responses: [ Time Frame: 12 weeks ]
- Plasma IFN-γ, GMCSF, IP-10, MIG, and MCP-1 changes [ Time Frame: from baseline and predose ]
- Plasma IL-18BP change [ Time Frame: from baseline ]
- PBMC phenotype changes [ Time Frame: from baseline and pre-dose ]
- Activated NK cells (CD16+/CD56+/CD3-/CD69+/FasL+ or IL-18Ra+) [ Time Frame: 12 weeks ]
- Activated cytolytic T cells (CD8+/CD4-/CD3+/CD69+ FasL+ or IL- 18Ra+) [ Time Frame: 12 weeks ]
- Activated B cells (CD19+/CD25-/CD3-/CD69+) [ Time Frame: 12 weeks ]
- Activated Neutrophils/Monocytes (CD11b+/CD16+/CD64+/CD14+/CD45+/CD69+) [ Time Frame: 12 weeks ]
- Regulatory T-cells (FoxP3+/CD25+/CD4+/CD127+) [ Time Frame: 12 weeks ]
- Immunogenicity (anti-SB-485232 and anti-Rituximab antibodies) [ Time Frame: 12 weeks ]
- Anti-tumor activity (Radiographic tumor assessments) [ Time Frame: 12 weeks ]
- CD16 (FcγRIIIA) 158V/F genotyping [ Time Frame: 12 weeks ]
| Study Start Date:
| Study Completion Date:
| Primary Completion Date:
||March 2010 (Final data collection date for primary outcome measure)
Drug: interleukin-18, Rituxan, Rituximab
|Ages Eligible for Study:
||18 Years and older
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- 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 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00500058
|GSK Investigational Site
|Chicago, Illinois, United States, 60637 |
|GSK Investigational Site
|Indianapolis, Indiana, United States, 46202 |
||GSK Clinical Trials
No publications provided
History of Changes
|Other Study ID Numbers:
|Study First Received:
||July 10, 2007
||May 31, 2012
||United States: Food and Drug Administration
Keywords provided by GlaxoSmithKline:
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on December 05, 2013
Neoplasms by Histologic Type
Immune System Diseases
Physiological Effects of Drugs