Tocilizumab for KSHV-Associated Multicentric Castleman Disease
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|ClinicalTrials.gov Identifier: NCT01441063|
Recruitment Status : Recruiting
First Posted : September 27, 2011
Last Update Posted : February 13, 2020
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Castleman Disease Castleman's Disease Giant Lymph Node Hyperplasia||Drug: Zidovudine Drug: Tocilizumab Drug: Valganciclovir (VGC)||Phase 2|
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||17 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Pilot Study of Tocilizumab in Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV) - Associated Multicentric Castleman Disease|
|Actual Study Start Date :||September 13, 2011|
|Estimated Primary Completion Date :||July 1, 2021|
|Estimated Study Completion Date :||July 1, 2023|
Tocilizumab 8 mg/kg on Day 1 of a 14 day cycle a maximum of 6 cycles. If indicated, AZT and VGC will be administered concurrently with toclizumab, with day 1 of the cycle being the day toclizumab is administered.
Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours)
Tocilizumab 8mg/kg every 2 weeks
Drug: Valganciclovir (VGC)
Valganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle.
- Determine the efficacy of tocilizumab in the treatment of KSHV-MCD. [ Time Frame: every 2 weeks for up to 12 weeks ]Evaluation of MCD clinical and biochemical response at each visit using a modified KSHV- MCD Clinical Benefit Response Criteria.
- Best clinical, biochemical, radiographic, and overall response [ Time Frame: up to 12 weeks ]Evaluate best clinical, biochemical, radiographic, and overall response in patients with KSHV- associated MCD treated for up to 12 weekswith tocilizumab 8mg/kg every 2 weeks using the prior NCI KSHV-MCD Response Criteria
- Effect of tocilizumab + AZT [ Time Frame: days 1-5 of a 14-day cycle ]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 in patients with inadequate response to tocilizumab monotherapy
- Safety and tolerability [ Time Frame: each cycle ]Evaluate safety and tolerability of tocilizumab alone and in combination with AZT/VGC in patients with inadequate response to tocilizumabmonotherapy
- Effect of tocilizumab on the PK of antiretroviral agents [ Time Frame: C1D1, C2-6 D1 ]Evaluate the effect of tocilizumab on the pharmacokinetics ofantiretroviral agents that are CYP3A4 substrates in patients with symptomatic KSHV-MCD
- Effect of tocilizumab on KS [ Time Frame: Baseline, week 7, and at offstudy visit ]Evaluate the best KS response, using modified ACTG Response criteria in patients with concurrent Kaposi sarcoma
- Progression-free and overall survival [ Time Frame: 4 months ]Evaluate progression-free and overall survival with tocilizumab and tocilizumab /AZT/VGC
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01441063
|Contact: Anaida Widell||(301) firstname.lastname@example.org|
|Contact: Robert Yarchoan, M.D.||(240) email@example.com|
|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:||Robert Yarchoan, M.D.||National Cancer Institute (NCI)|