Tocilizumab for KSHV-Associated Multicentric Castleman Disease
关键词
抽象
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
- Pathologically confirmed KSHV-associated MCD
- Age greater than or equal to 18
- At least one clinical symptom and at least one laboratory attributable to KSHV-MCD
- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
- No life- or organ-threatening manifestations of MCD
- Patients requiring therapy for rheumatoid arthritis will be excluded
- HIV-infected patients must agree to continue or start combination antiretroviral therapy
DESIGN:
- Open label, single center pilot study. Eligible patients receive tocilizumab 8 mg/kg every 2 weeks for up to 12 weeks. In addition, patients requiring treatment intensification also receive AZT 600 mg orally q6 hours and VGC 900 mg orally q12 hours on days 1-5 of a 14-day cycle.
- Sample size 17: two stage phase II design, alpha equals beta equals 0.10, ruling out <20% KSHV-MCD Clinical Benefit Partial Response or better with tocilizumab and targeting a >50% KSHV-MCD Clinical Benefit Partial Response or better requires 10 in the first stage. 0-2 of 10 major response: stop accrual, 3+/10: accrual to 17 total.
- Responses evaluated by KSHV-MCD Clinical Benefit Response Criteria and NCI KSHV-MCD criteria under prospective evaluation.
- Safety and tolerability evaluated using current Common Terminology Criteria for Adverse Events (CTCAE).
日期
最后验证: | 05/31/2020 |
首次提交: | 09/23/2011 |
提交的预估入学人数: | 09/23/2011 |
首次发布: | 09/26/2011 |
上次提交的更新: | 06/10/2020 |
最近更新发布: | 06/22/2020 |
首次提交结果的日期: | 04/13/2020 |
首次提交质量检查结果的日期: | 06/10/2020 |
首次发布结果的日期: | 06/22/2020 |
实际学习开始日期: | 09/12/2011 |
预计主要完成日期: | 06/05/2018 |
预计完成日期: | 06/30/2023 |
状况或疾病
干预/治疗
Drug: Tocilizumab
Drug: Tocilizumab
Drug: Tocilizumab
相
手臂组
臂 | 干预/治疗 |
---|---|
Experimental: 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. | Drug: Tocilizumab Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours) |
资格标准
有资格学习的年龄 | 18 Years 至 18 Years |
有资格学习的性别 | All |
接受健康志愿者 | 是 |
标准 | - INCLUSION CRITERIA: - Pathologically confirmed Kaposi sarcoma (KS)-associated herpes virus multi-centric Castleman disease (KSHV-MCD) - Age greater than or equal to 18 - At least one clinical symptom probably or definitely attributed to KSHV-MCD - Intermittent or persistent fever for at least 1 week (>38 degrees C) - Fatigue (Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater) - Gastrointestinal symptoms [includes nausea and anorexia] (CTCAE Grade 1 or greater) - Respiratory symptoms [includes cough and airway hyperreactivity] (CTCAE Grade 1 or greater) - At least one laboratory abnormality probably or definitely attributed to KSHVMCD - Anemia (Hgb [men] =12.5 gm/dL, Hgb [women] = 11 gm/dL) - Thrombocytopenia (=130,000/mm(3)) - Hypoalbuminemia (<3.4 g/dl) - Elevated C-reactive protein (CRP) (CRP > 3 mg/L)] probably or definitely attributable to KSHV-MCD - No life- or organ-threatening manifestations of MCD - Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 - Human Immunodeficiency Virus (HIV)-infected patients should be receiving or willing to initiate an effective combination antiretroviral therapy (cART) regimen - Willingness to complete tuberculosis evaluation and start prophylactic antituberculosis therapy as soon as is medically feasible if patients have a reactive tuberculin skin test and have not completed an adequate course of prevented anti-tuberculosis therapy, following American Thoracic Society/ Centers for Disease Control recommended guidelines: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5231a4.htm - Ability to understand and willingness to give informed consent - Women of child bearing potential must agree to use birth control for the duration of the study EXCLUSION CRITERIA: - Uncontrolled bacterial, mycobacterial, or fungal infection - Uncontrolled intercurrent illness including, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or ability to receive therapy. - Pregnant or lactating women - Any abnormality that would be scored as National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Grade 3 toxicity that is unrelated to HIV, its treatment, or to MCD that would preclude protocol treatment. Exceptions include: - Lymphopenia - Direct manifestations of Kaposi sarcoma or MCD - Direct manifestation of HIV (i.e. low cluster of differentiation 4 (CD4) count) - Direct manifestation of HIV therapy (i.e. Hyperbilirubinemia associated with protease inhibitors) - Asymptomatic hyperuricemia - Hypophosphatemia - Elevated creatine kinase (CK) attributed to exercise - Past or present history of malignant tumors other than Kaposi sarcoma unless one of the following: - Complete remission for greater than or equal to 1 year from completion of therapy - Completely resected basal cell carcinoma - In situ squamous cell carcinoma of the cervix or anus - Patients with concurrent Kaposi sarcoma requiring immediate cytotoxic chemotherapy - History of tocilizumab therapy within prior three months - History of rituximab or bevacizumab therapy within three months - History of greater than or equal to 2 allergic reaction or any grade anaphylactic reaction during prior administration of tocilizumab |
结果
主要结果指标
1. Percentage of Participants With an Overall Clinical Benefit Response [every 2 weeks for up to 12 weeks]
次要成果指标
1. Percentage of Participants With a Clinical Response [up to 12 weeks]
2. Percentage of Participants With a Biochemical Response [up to 12 weeks]
3. Percentage of Participants With a Radiographic Response [up to 12 weeks]
4. 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.]
5. 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.]
6. 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.]
7. 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.]
8. 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.]
9. Percentage of Participants With Grade 3 or Greater Serious Adverse Events [each cycle, up to 6 years, 8 months and 24 days.]
10. Percentage of Participants With 11. 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.] 12. Effect of Tocilizumab on the Pharmacokinetics (PK) of Antiretroviral Agents [Cycle 1, Day 1 and Cycle 2-6 Day 1] 13. Percentage of Participants Progression-free Survival at 4 Months [4 months] 14. Percentage of Participants With Overall Survival 4 Months After Treatment With Tocilizumab and Tocilizumab /Zidovudine (AZT)/Valganciclovir (VGC) [4 months]