Pilot Study of Tocilizumab in Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV) - Associated Multicentric Castleman Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Percentage of Participants With an Overall Clinical Benefit Response
研究概览
简要总结
Background:
- Kaposi's sarcoma-associated herpes virus (KSHV)-associated multicentric Castleman disease (KSHV-MCD) is caused by a herpes virus known as KSHV. This disease can also cause several other cancers, including Kaposi sarcoma. People with KSHV-MCD often have symptoms like fever, weight and muscle loss, and fluid in the legs or abdomen. Tocilizumab may be able to block the chemicals in the body that cause KSHV-MCD symptoms. Researchers want to test this drug and other anti-virus drugs to find the best combination of drugs to treat KSHV-MCD.
Objectives:
- To test the effectiveness of tocilizumab with and without other anti-virus drugs for KSHV-MCD.
Eligibility:
- People at least 18 years of age who have KSHV-MCD and have certain symptoms and blood abnormalities caused by their KSHV-MCD.
Design:
- Participants will be screened with a medical history and physical exam. They will also have blood tests, and a skin biopsy.
- Participants will have tocilizumab injections every 2 weeks for up to 12 weeks. They will provide daily blood samples for the first 3 days of treatment.
- After the sixth dose, participants will be monitored for 4 weeks to check for possible side effects.
- Those whose KSHV-MCD does not improve or worsens during the study may have tocilizumab combined with two other anti-virus drugs, zidovudine and valganciclovir. These drugs are pills that will be taken four times a day for 5 days out of every 2 weeks.
- Blood, urine, and saliva samples will be collected throughout the study.
详细描述
BACKGROUND:
- Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHVMCD) is a rare lymphoproliferative disorder that develops predominantly in human immunodeficiency deficiency virus (HIV) infected patients. Patients often have symptoms from interleukin-6 (IL-6), KSHV encoded viral IL-6 (vIL-6), and other cytokines
- Goals of therapy include rapid resolution symptoms and elimination of reservoirs of KSHV-infected plasmablasts.
- Tocilizumab is a humanized anti-IL-6 receptor (gp80) antibody with activity against MCD unrelated to KSHV (KSHV-negative MCD). While tocilizumab does not directly affect vIL-6 signaling or other KSHV driven pathologic processes, IL-6 overproduction plays a major role in symptoms in KSHV-MCD, and blocking IL-6 may be sufficient to treat this disorder by blocking autocrine and paracrine stimulation. Combination with zidovudine (AZT) and valganciclovir (VGC), agents that target KSHV replication, have virus-activated cytotoxic activity, and are active in KSHV-MCD may be useful and necessary in some patients.
OBJECTIVES:
- Primary objective: Estimate clinical benefit of tocilizumab 8mg/kg every 2 weeks for up to 12 weeks in patients with symptomatic KSHV-MCD using a modified KSHVMCD Clinical Benefit Response Criteria
- Secondary objectives:
- Estimate best clinical, biochemical, radiographic, and overall responses in patients with KSHV-MCD treated for up to 12 weeks with tocilizumab 8mg/kg every 2 weeks using the prior National Cancer Institute (NCI) KSHV-MCD Response Criteria.
- In patients with inadequate response to tocilizumab monotherapy: explore preliminarily the activity of tocilizumab 8mg/kg every 2 weeks, combined with AZT 600 mg orally q6 hours and VGC 900 mg orally q12 hours on days 1-5 of a 14-day cycle
- Evaluate safety and tolerability of tocilizumab alone and combined with AZT/VGC
- Evaluate the effect of tocilizumab on the pharmacokinetics of antiretroviral agents that are Cytochrome P450 3A4 (CYP3A4) substrates in patients with symptomatic KSHV-MCD
- Evaluate progression-free and overall survival of patients treated with tocilizumab and tocilizumab/AZT/VGC
- Evaluate of effect of tocilizumab on KS
Eligibility
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Tocilizumab
Tocilizumab 8 mg/kg on Day 1 of a 14 day cycle a maximum of 6 cycles. If indicated, zidovudine (AZT) and valganciclovir (VGC) will be administered concurrently with tocilizumab, with day 1 of the cycle being the day tocilizumab is administered.
干预措施: Zidovudine (Drug)
Tocilizumab
Tocilizumab 8 mg/kg on Day 1 of a 14 day cycle a maximum of 6 cycles. If indicated, zidovudine (AZT) and valganciclovir (VGC) will be administered concurrently with tocilizumab, with day 1 of the cycle being the day tocilizumab is administered.
干预措施: Tocilizumab (Drug)
Tocilizumab
Tocilizumab 8 mg/kg on Day 1 of a 14 day cycle a maximum of 6 cycles. If indicated, zidovudine (AZT) and valganciclovir (VGC) will be administered concurrently with tocilizumab, with day 1 of the cycle being the day tocilizumab is administered.
干预措施: Valganciclovir (VGC) (Drug)
结局指标
主要结局
Percentage of Participants With an Overall Clinical Benefit Response
时间窗: every 2 weeks for up to 12 weeks
Overall clinical benefit response is defined as Complete Response (CR): Full resolution of all clinical symptoms and laboratory abnormalities (whether or not these are indicator abnormalities) probably or definitely attributable to MCD, lasting at least 3 weeks; and Partial Response (PR): At least 50% of the abnormalities probably or definitely attributed to KSHV-MCD must improve by the minimum amounts specified to attain PR. Only abnormalities present in a specific patient at baseline may count toward the achievement of a PR (e.g. if six of indicator abnormalities are present at baseline, at least three must meet the specified criteria to be considered a PR) assessed using a modified Kaposi sarcoma herpes virus-associated multicentric Castleman disease (KSHV- MCD) Clinical Benefit Response Criteria and the National Cancer Institute (NCI) KSHV-MCD criteria.
次要结局
- Percentage of Participants With a Clinical Response(up to 12 weeks)
- Percentage of Participants With a Biochemical Response(up to 12 weeks)
- Percentage of Participants With a Radiographic Response(up to 12 weeks)
- Percentage of Participants With Kaposi Sarcoma Responses Per the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Response Criteria(Baseline, week 7, and at off study visit, approximately 2 weeks following last study treatment for those with KS, up to 14 weeks.)
- Changes in Plasma Exposure of Ritonavir in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450)(Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.)
- Changes in Plasma Exposure of Lopinavir in Response to Tocilizumab and AZT Metabolized by Cytochrome P450 (CYP450)(Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.)
- Changes in Plasma Exposure of Atazanavir in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450)(Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.)
- Changes in Plasma Exposure of Efavirenz in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450)(Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.)
- Percentage of Participants With Grade 3 or Greater Serious Adverse Events(each cycle, up to 6 years, 8 months and 24 days.)
- Percentage of Participants With <Grade 3 Non- Serious Adverse Events(each cycle, up to 6 years, 8 months and 24 days.)
- Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)(Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.)
- Effect of Tocilizumab on the Pharmacokinetics (PK) of Antiretroviral Agents(Cycle 1, Day 1 and Cycle 2-6 Day 1)
- Percentage of Participants Progression-free Survival at 4 Months(4 months)
- Percentage of Participants With Overall Survival 4 Months After Treatment With Tocilizumab and Tocilizumab /Zidovudine (AZT)/Valganciclovir (VGC)(4 months)
研究者
Robert Yarchoan
Principal Investigator
National Cancer Institute (NCI)