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Tocilizumab for KSHV-Associated Multicentric Castleman Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01441063
First received: September 24, 2011
Last updated: July 19, 2014
Last verified: March 2014
  Purpose

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 Intervention Phase
Castleman Disease
Castleman's Disease
Giant Lymph Node Hyperplasia
Drug: Zidovudine
Drug: Tocilizumab
Drug: Valganciclovir
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot Study of Tocilizumab in Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV) - Associated Multicentric Castleman Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 [ Time Frame: 4 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Estimate radiographic responses [ Time Frame: 4 years ] [ Designated as safety issue: No ]
  • Explore activity of tocilizumab combined with AZT/VGC [ Time Frame: 4 years ] [ Designated as safety issue: No ]
  • Evaluate safety and tolerability [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
  • Evaluate effect of tocilizumab on PK of select antiretronial agents. [ Time Frame: 4 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 17
Study Start Date: August 2011
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Zidovudine
    600 mg orally every 6 hours, days 1-5
    Drug: Tocilizumab
    8 mg/kg IV every 14 days
    Drug: Valganciclovir
    900 mg orally every 12 hours, days 1-5
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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01441063

Contacts
Contact: Karen Aleman, R.N. (301) 496-8959 alemank@mail.nih.gov
Contact: Thomas S Uldrick, M.D. (301) 402-6296 uldrickts@mail.nih.gov

Locations
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
Investigators
Principal Investigator: Thomas S Uldrick, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01441063     History of Changes
Other Study ID Numbers: 110233, 11-C-0233
Study First Received: September 24, 2011
Last Updated: July 19, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Kaposi Sarcoma Herpesvirus
Human Immunodeficiency Virus
Tocilizumab
Multicentric Castleman Disease
Interleukin-6
Castleman Disease

Additional relevant MeSH terms:
Giant Lymph Node Hyperplasia
Hyperplasia
Sarcoma, Kaposi
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pathologic Processes
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Vascular Tissue
Zidovudine
Valganciclovir
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on July 28, 2014