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).
