Tocilizumab for 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 ]
  

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.