Tocilizumab for KSHV-Associated Multicentric Castleman Disease

• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

Background:

- 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.

Objectives:

- To test the effectiveness of tocilizumab with and without other anti-virus drugs for KSHV-MCD.

Eligibility:

- People at least 18 years of age who have KSHV-MCD and have certain symptoms and blood abnormalities caused by their KSHV-MCD.

Design:

• 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

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	17 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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, 2020
Estimated Study Completion Date :	July 1, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; 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.	Drug: Zidovudine; Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours); Drug: Tocilizumab; 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.

Outcome Measures

Primary Outcome Measures :

1. 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 99 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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 [men] </=12.5 gm/dL, Hgb [women] </= 11 gm/dL)
• Thrombocytopenia (</=130,000/mm(3))
• Hypoalbuminemia (<3.4 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

Contacts and Locations

Contacts

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Contact: Anaida Widell	(301) 451-3694	awidell@cc.nih.gov
Contact: Robert Yarchoan, M.D.	(240) 760-6075	robert.yarchoan@nih.gov

Locations

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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

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

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Principal Investigator:	Robert Yarchoan, M.D.	National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP, Agbalika F. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients. Blood. 2000 Sep 15;96(6):2069-73.

Uldrick TS, Wang V, O'Mahony D, Aleman K, Wyvill KM, Marshall V, Steinberg SM, Pittaluga S, Maric I, Whitby D, Tosato G, Little RF, Yarchoan R. An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without Multicentric Castleman disease. Clin Infect Dis. 2010 Aug 1;51(3):350-8. doi: 10.1086/654798.

Brandt SJ, Bodine DM, Dunbar CE, Nienhuis AW. Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice. J Clin Invest. 1990 Aug;86(2):592-9.

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT01441063 History of Changes
Other Study ID Numbers:	110233; 11-C-0233
First Posted:	September 27, 2011
Last Update Posted:	February 15, 2019
Last Verified:	November 30, 2018

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Kaposi Sarcoma Herpesvirus; Human Immunodeficiency Virus; Tocilizumab	Multicentric Castleman Disease; Interleukin-6; Castleman Disease

Additional relevant MeSH terms:

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Hyperplasia; Castleman Disease; Pathologic Processes; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Zidovudine; Valganciclovir	Antimetabolites; Molecular Mechanisms of Pharmacological Action; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Anti-HIV Agents