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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Castleman Disease, Castleman's Disease, Giant Lymph Node Hyperplasia

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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.

Inclusion Criteria


- INCLUSION CRITERIA:

- Pathologically confirmed KSHV-MCD

- Age greater than or equal to 18

- At least one clinical symptom probably or definitely attributed to KSHV-MCD

- Intermittent or persistent fever for at least 1 week (> 38 degrees C)

- Fatigue (CTCAE Grade 2 or greater)

- Gastrointestinal symptoms [includes nausea and anorexia] (CTCAE Grade 1 or greater)

- Respiratory symptoms [includes cough and airway hyperreactivity]

(CTCAE Grade 1 or greater)

- At least one laboratory abnormality probably or definitely attributed to KSHVMCD

- Anemia (Hgb < 11.0 g/dL)

- Thrombocytopenia (< 100,000/mm(3))

- Hypoalbuminemia (< 3.3 g/dl)

- Elevated C-reactive protein (CRP) (CRP > 3 mg/L)] probably or definitely
attributable to KSHV-MCD

- No life- or organ-threatening manifestations of MCD

- ECOG performance status less than or equal to 2

- HIV-infected patients should be receiving or willing to initiate an effective
combination antiretroviral therapy (cART) regimen

- Willingness to complete tuberculosis evaluation and start prophylactic
antituberculosis therapy as soon as is medically feasible if patients have a reactive
tuberculin skin test and have not completed an adequate course of prevented
anti-tuberculosis therapy, following American Thoracic Society / Centers for

Disease Control recommended guidelines:

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5231a4.htm

- Ability to understand and willingness to give informed consent

- Women of child bearing potential must agree to use birth control for the duration of
the study

EXCLUSION CRITERIA:

- Uncontrolled bacterial, mycobacterial, or fungal infection

- Uncontrolled intercurrent illness including, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements or ability to receive
therapy.

- Pregnant or lactating women

- Any abnormality that would be scored as NCI CTC Grade 3 toxicity that is unrelated to
HIV, its treatment, or to MCD that would preclude protocol treatment. Exceptions
include:

- Lymphopenia

- Direct manifestations of Kaposi sarcoma or MCD

- Direct manifestation of HIV (i.e. low CD4 count)

- Direct manifestation of HIV therapy (i.e. Hyperbilirubinemia associated with protease
inhibitors)

- Asymptomatic hyperuricemia

- Hypophosphatemia

- Elevated CK attributed to exercise

- Past or present history of malignant tumors other than Kaposi sarcoma unless one of
the following:

- Complete remission for greater than or equal to 1 year from completion of therapy

- Completely resected basal cell carcinoma

- In situ squamous cell carcinoma of the cervix or anus

- Patients with concurrent Kaposi sarcoma requiring immediate cytotoxic chemotherapy

- History of tocilizumab therapy within prior three months

- History of rituximab or bevacizumab therapy within three months

- History of greater than or equal to 2 allergic reaction or any grade anaphylactic
reaction during prior administration of tocilizumab

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Estimate clinical benefit of tocilizumab 8mg/kg every 2 weeks for up to 12 weeks in patients with symptomatic KSHV-MCD using a modified KSHV-MCD Clinical Benefit Response Criteria

Outcome Time Frame:

4 years

Safety Issue:

No

Principal Investigator

Thomas S Uldrick, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110233

NCT ID:

NCT01441063

Start Date:

August 2011

Completion Date:

July 2015

Related Keywords:

  • Castleman Disease
  • Castleman's Disease
  • Giant Lymph Node Hyperplasia
  • Kaposi Sarcoma Herpesvirus
  • Human Immunodeficiency Virus
  • Tocilizumab
  • Multicentric Castleman Disease
  • Interleukin-6
  • Castleman Disease
  • Giant Lymph Node Hyperplasia
  • Hyperplasia
  • Sarcoma, Kaposi

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892