Trial Information

Pilot Study of Tocilizumab in Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV) - Associated Multicentric Castleman Disease

BACKGROUND:

- 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.

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 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

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

- 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 CTCAE.