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

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"

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma, Non-Hodgkin
• Intervention / Treatment: Drug: SB-485232; Drug: Rituximab

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • GSK Investigational Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Robertson MJ, Kline J, Struemper H, Koch KM, Bauman JW, Gardner OS, Murray SC, Germaschewski F, Weisenbach J, Jonak Z, Toso JF. A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma. J Immunother. 2013 Jul-Aug;36(6):331-41. doi: 10.1097/CJI.0b013e31829d7e2e.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2007
• Primary Completion (Actual): March 4, 2010
• Study Completion (Actual): March 4, 2010

Study Registration Dates

• First Submitted: July 10, 2007
• First Submitted That Met QC Criteria: July 10, 2007
• First Posted (Estimate): July 12, 2007

Study Record Updates

• Last Update Posted (Actual): July 26, 2017
• Last Update Submitted That Met QC Criteria: July 24, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: oncology; IL-18,; combination study,; cytokine,; Rituximab,
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: ILI105618

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Study Protocol
   Information identifier: ILI105618
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Annotated Case Report Form
   Information identifier: ILI105618
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Informed Consent Form
   Information identifier: ILI105618
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Statistical Analysis Plan
   Information identifier: ILI105618
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Individual Participant Data Set
   Information identifier: ILI105618
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Clinical Study Report
   Information identifier: ILI105618
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Dataset Specification
   Information identifier: ILI105618
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register