Tocilizumab for KSHV-Associated Multicentric Castleman Disease
- 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.
- To test the effectiveness of tocilizumab with and without other anti-virus drugs for KSHV-MCD.
- People at least 18 years of age who have KSHV-MCD and have certain symptoms and blood abnormalities caused by their KSHV-MCD.
- 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.
Giant Lymph Node Hyperplasia
Drug: Valganciclovir (VGC)
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pilot Study of Tocilizumab in Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV) - Associated Multicentric Castleman Disease|
- Determine the efficacy of tocilizumab in the treatment of KSHV-MCD. [ Time Frame: Evaluation of MCD clinical and biochemical response at each visit. ] [ Designated as safety issue: No ]
- Estimate best clinical, biochemical, radiographic and overall response. [ Time Frame: Clinical and laboratory responses are assessed in aggregate and compared to baseline. ] [ Designated as safety issue: No ]
- Evaluate progression-free and overall survival with tocilizumab and tocilizumab/AZT/VGC. [ Time Frame: Time interval from the date of enrollment to the date of progression from best response. ] [ Designated as safety issue: No ]
- Evaluate safety and tolerability of tocilizumab alone and in combination with AZT/VGC [ Time Frame: Toxicities will be evaluated both per cycle and per patient. ] [ Designated as safety issue: Yes ]
- Evaluate the effect of tocilizumab on the pharmacokinetics of antiretroviral agents that are CYP3A4 substrates in patients with symptomatic KSHVMCD [ Time Frame: Cycle 1, Day 1, Day 3, Cycles 2--6 ] [ Designated as safety issue: Yes ]
- Evaluate effect of tocilizumab on KS [ Time Frame: Baseline, week 7 and at off-study ] [ Designated as safety issue: No ]
|Study Start Date:||August 2011|
|Estimated Study Completion Date:||July 2018|
|Estimated Primary Completion Date:||July 2016 (Final data collection date for primary outcome measure)|
Patients with KSHV-MCD
Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours)Drug: Tocilizumab
Tocilizumab 8mg/kg every 2 weeksDrug: Valganciclovir (VGC)
Valganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle.
- Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHVMCD) is a rare lymphoproliferative disorder that develops predominantly in HIVinfected patients. Patients often have symptoms from interleukin-6 (IL-6), KSHVencoded 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.
- 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 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 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
- 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
- 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
- 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 CTCAE.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01441063
|Contact: Karen Aleman, R.N.||(301) email@example.com|
|Contact: Thomas S Uldrick, M.D.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937|
|Principal Investigator:||Thomas S Uldrick, M.D.||National Cancer Institute (NCI)|